RU2625790C2 - New pyrazole derivative - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: in particular, invention relates to a compound represented by the following general formula (I):

[wherein Ar¹ is 2-methoxy-4-(2-pyridylmethoxy)phenyl, etc. and Ar² is 1H-indole-6-yl group, etc.] or to salt thereof.

EFFECT: increased efficiency of treatment.

19 cl, 4 dwg, 1 tbl, 112 ex

Description

Technical field

The present invention relates to a new compound; tau aggregation inhibitor, β-secretase inhibitor, and amyloid β-protein aggregation inhibitor using this compound; and a pharmaceutical composition using this compound for the prevention or treatment of diseases such as dementia and Alzheimer's disease.

State of the art

Senile dementia has become a serious medical and social problem along with the rapid aging of society in recent years, and the development of effective medicines against dementia has become highly desirable. A lot of research has already been done on Alzheimer's disease, but the cause of this disease has not been clearly defined. The drug against Alzheimer's disease, Arisept, is based on its inhibitory activity against acetylcholinesterase. This medicine is very useful as a remedy for symptomatic treatment, but not as a medicine for fundamental therapy.

Alzheimer's disease is believed to be caused by aggregation of amyloid β protein (hereinafter also referred to as Aβ), tau aggregation, and the like. Therefore, a substance that can inhibit the aggregation of these proteins is a potential candidate as a fundamental therapeutic agent for the treatment of Alzheimer's disease.

Yang et al. reported that curcumin has inhibitory activity against Aβ aggregation, disaggregation activity against Aβ aggregates, and the like. (Non-Patent Literature 1). The inventors have disclosed that curcumin and its derivatives have inhibitory activity against secretase, which is involved in the generation of Aβ (Patent Literature 1 and 2). Narlawar et al. curcumin derivatives were synthesized by replacing the 1,3-dicarbonyl group with a pyrazole ring, and these compounds were reported to have tau aggregation inhibitory activity (Non-Patent Literature 2).

Bibliography

Patent Literature

Patent Literature 1: WO2008 / 066151.

Patent Literature 2: WO2009 / 145219.

Non-Patent Literature

Non-Patent Literature 1:

Fusheng Yang et al., J. Biol. Chem. 2005, Feb 18; 280 (7) 5892-5901.

Non-Patent Literature 2:

Rajeshwar Narlawar et al., ChemMedChem 2008, 3, 165-172.

SUMMARY OF THE INVENTION

Technical challenge

As described in the above literature, a curcumin derivative may be a promising candidate as a fundamental therapeutic agent for the treatment of Alzheimer's disease. With this level of technology, the aim of the present invention is, therefore, to obtain a new therapeutic agent for the treatment of Alzheimer's disease.

The solution of the problem

The inventors succeeded in creating a new compound that is different from the known compounds, and found that this compound has excellent pharmacological activity. The inventors further conducted extensive research to implement the present invention.

As a result of extensive studies to solve the above problems, the inventors synthesized a curcumin derivative, replacing the 1,3-dicarbonyl group of curcumin with a pyrazole ring and replacing at least one of the 4-hydroxy-3-methoxyphenyl groups at both ends with a substituent, and found that the derivative Curcumin has potent inhibitory activity against tau aggregation. The inventors also found that this derivative has high penetration into the brain and also has inhibitory activity against β-secretase and inhibitory activity against Aβ aggregation.

A curcumin derivative in which the 1,3-dicarbonyl group of curcumin is replaced with a pyrazole ring is described in Non-Patent Literature 2, etc. A curcumin derivative in which one of the 4-hydroxy-3-methoxyphenyl groups at both ends of the curcumin is replaced with a substituent is described in Patent Literature 1 and 2, etc. However, a curcumin derivative that has a pyrazole ring and in which at least one of the 4-hydroxy-3-methoxyphenyl groups at both ends is substituted with a substituent is a new compound that has not been disclosed in the literature.

The inhibitory activity of the curcumin derivative with respect to tau aggregation is described in Non-Patent Literature 2. In this literature, the nitrogen atom at position 1 of the pyrazole ring is replaced by different groups, and the inhibitory activities of the derivatives with respect to tau aggregation vary significantly depending on the groups introduced into the ring. However, no modification of the benzene rings at both ends was made, and thus all synthesized derivatives have 4-hydroxy-3-methoxyphenyl groups, like curcumin. Therefore, it is expected that a person familiar with Non-Patent Literature 2 will believe that the group introduced into the pyrazole ring plays an important role for the inhibitory activity against tau aggregation and that the 4-hydroxy-3-methoxyphenyl groups at both ends are not relevant for inhibitory activity against aggregation of tau. Thus, a specialist would not attempt to replace 4-hydroxy-3-methoxyphenyl groups with a substituent.

The present invention has been made based on the above findings.

Thus, the present invention relates to the following.

[1] A compound represented by the following general formula (I):

[in which R is hydrogen having a chain or a cyclic hydrocarbon group, optionally having a substituent, or a heterocyclic group, optionally having a substituent; and

Ar ¹ and Ar ² are the same or different, and each represents a homocyclic or heterocyclic group, optionally having a substituent;

except where R is hydrogen, and Ar ¹ and Ar ² are each a 4-hydroxy-3-methoxyphenyl group]

or its salt.

[2] The compound or its salt according to paragraph [1], wherein R in the general formula (I) is hydrogen.

[3] The compound or its salt according to paragraph [1] or [2], wherein Ar ¹ in the general formula (I) is a phenyl group, optionally having a substituent.

[4] The compound or its salt according to [1] or [2], wherein Ar ¹ in the general formula (I) is a phenyl group having a C _1-3 alkyloxy group, optionally having a substituent.

[5] The compound or its salt according to [1] or [2], wherein Ar ¹ in the general formula (I) denotes a phenyl group having a C _1-3 alkyloxy group substituted with a heterocycloalkyl group, optionally having a substituent phenyl group having a C _1-3 alkyloxy group substituted by a cycloalkyl group, optionally having a substituent, phenyl group having a C _1-3 alkyloxy group substituted by a heteroaryl group, optionally having a substituent, phenyl group having a C _1-3 alkyloxy group substituted by aryl an optionally substituted group, a phenyl group having a C _1-3 alkyloxy group substituted with a dialkylamino group, optionally having a substituent, a phenyl group having a C _1-3 alkyloxy group substituted with an alkyloxy group, optionally having a substituent, or a phenyl group having a C _1-3 alkyloxy group substituted with an alkyl group, optionally having a substituent.

[6] The compound or its salt according to paragraph [1] or [2], wherein Ar ¹ in the general formula (I) is a phenyl group having a tetrahydrofuran-3-ylmethoxy group, tetrahydrofuran-2-ylmethoxy group, 2- (piperidin-1 -yl) ethoxy group, 2- (4-methylpiperazino) ethoxy group, 2- (4-benzylpiperazino) ethoxy group, 2-morpholinoethoxy group, 2-pyrrolidinoethoxy group, β-D-glucopyranosyloxy group, 2- [4- (tert-butoxycarbonyl) -yl] ethoxy group, 2- [4- (methylsulfonyl) piperazin-1-yl] ethoxy group or 2- [4- (2-hydroxyethyl) piperazin-1-yl] ethoxy group.

[7] The compound or its salt according to paragraph [1] or [2], wherein Ar ¹ in the general formula (I) is a 2-methoxy-4- (tetrahydrofuran-3-ylmethoxy) phenyl group, 2-methoxy-4- (tetrahydrofuran-2-ylmethoxy) phenyl group, 2-methoxy-4- [2- (piperidin-1-yl) ethoxy] phenyl group, 2-methoxy-4- [2- (4-methylpiperazino) ethoxy] phenyl group, 2-methoxy-4- (2-morpholinoethoxy) phenyl group, 4- (β-D-glucopyranosyl) oxy-2-methoxyphenyl group, 4- (tetrahydrofuran-3-ylmethoxy) phenyl group, 4- (tetrahydrofuran-2-ylmethoxy ) phenyl group, 3-methoxy-4- (tetrahydrofuran-3-ylmetho xi) phenyl group, 3-methoxy-4- (tetrahydrofuran-2-ylmethoxy) phenyl group, 2- [2- (4-benzylpiperazino) ethoxy] -4-methoxyphenyl group, 4-diethylamino-2- (2-morpholinoethoxy) phenyl group, 4-dimethylamino-2- (2-morpholinoethoxy) phenyl group, 4-diethylamino-2- (2-morpholinoethoxy) phenyl group, 4-diethylamino-2- (2-pyrrolidinoethoxy) phenyl group or 4-diethylamino-2 - [2- (piperidin-1-yl) ethoxy] phenyl group.

[8] The compound or its salt according to paragraph [1] or [2], wherein Ar ¹ in the general formula (I) represents a phenyl group having a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, a pyridin-4-ylmethoxy group, or 1-pyrrolylmethoxy group.

[9] The compound or its salt according to paragraph [1] or [2], wherein Ar ¹ in the general formula (I) is a 4- (pyridin-2-ylmethoxy) phenyl group, 2-methoxy-4- (pyridin-2 -ylmethoxy) phenyl group, 2- [2- (piperidin-1-yl) ethoxy] -4- (pyridin-2-ylmethoxy) phenyl group, 2- (2-morpholinoethoxy) -4- (pyridin-2-ylmethoxy) phenyl group, 2- (2-pyrrolidinoethoxy) -4- (pyridin-2-ylmethoxy) phenyl group, 2- [2- (4-methylpiperazino) ethoxy] -4- (pyridin-2-ylmethoxy) phenyl group, 3- methoxy-4- (pyridin-2-ylmethoxy) phenyl group, 2-hydroxy-4- (pyridin-2-ylmethoxy) phenyl group, 3- (pyridin-2-y methoxy) phenyl group, 2-methoxy-3- (pyridin-2-ylmethoxy) phenyl group, 4-methoxy-3- (pyridin-2-ylmethoxy) phenyl group, 3-methoxy-5- (pyridin-2-ylmethoxy) phenyl group, 2-methoxy-5- (pyridin-2-ylmethoxy) phenyl group, 2- (pyridin-2-ylmethoxy) phenyl group, 4-methoxy-2- (pyridin-2-ylmethoxy) phenyl group, 5-methoxy -2- (pyridin-2-ylmethoxy) phenyl group, 2-nitro-5- (pyridin-3-ylmethoxy) phenyl group, 4-diethylamino-2- (pyridin-3-ylmethoxy) phenyl group or 2-methoxy-2 - (1-pyrrolylmethoxy) phenyl group.

[10] The compound or its salt according to any one of [1] to [9], wherein Ar ² in the general formula (I) is a bicyclic homocyclic or heterocyclic group, optionally having a substituent.

[11] The compound or its salt according to any one of [1] to [9], wherein Ar ² in the general formula (I) is a bicyclic heterocyclic group, optionally having a substituent.

[12] The compound or its salt according to paragraph [11], wherein Ar ² in the general formula (I) represents an indol-2-yl group, indol-3-yl group, indol-4-yl group, indol-5-yl group, indol-6-yl group, indol-7-yl group, benzotriazol-5-yl group, benzimidazol-5-yl group, quinoxalin-6-yl group, benzofuran-2-yl group, benzothiophen-2-yl group , 1H-indazol-5-yl group, 7-azaindol-3-yl group, quinolin-2-yl group, quinolin-5-yl group, quinolin-8-yl group, 1,4-benzodioxan-6-yl group , 1,3-benzodioxol-5-yl group y, chromone-3-yl group, a coumarin-6-yl group, 7-methoxycoumarin-4-yl group or a 4-methoxycoumarin-6-yl group.

[13] The compound or its salt according to paragraph [11], wherein Ar ² in the general formula (I) represents a bicyclic heterocyclic group having a methyl group, ethyl group, benzyl group, acetyl group, benzoyl group, tert-butoxycarbonyl group, methylsulfonyl a group, a p-toluenesulfonyl group, a hydroxyl group or a nitro group.

[14] The compound or its salt according to paragraph [11], wherein Ar ² in the general formula (I) is a 1-methylindol-6-yl group, 1-methylindol-2-yl group, 1-methylindol-3-yl group , 1-ethylindol-6-yl group, 1-benzylindol-3-yl group, 1-benzylindol-6-yl group, 1-acetylindol-3-yl group, 1-acetylindol-6-yl group, 1-benzoylindol- 3-yl group, 1-tert-butoxycarbonylindol-5-yl group, 1-methylsulfonylindol-3-yl group, 1-methylsulfonylindol-6-yl group, 1-p-toluenesulfonylindol-3-yl group, 1-p-toluenesulfonylindole -6-yl g uppu, 4-hydroxyindole-3-yl group or 4-nitroindole-3-yl group.

[15] A tau aggregation inhibitor comprising a compound or a salt thereof according to any one of [1] to [14] as an active ingredient.

[16] A β-secretase inhibitor comprising a compound or its salt according to any one of [1] to [14] as an active ingredient.

[17] An amyloid β-protein aggregation inhibitor comprising a compound or a salt thereof according to any one of [1] to [14] as an active ingredient.

[18] A pharmaceutical composition comprising a compound or a salt thereof according to any one of [1] to [14] as an active ingredient.

[19] The pharmaceutical composition according to paragraph [18] for use in the prevention or treatment of a disease in which tau, β-secretase or amyloid β-protein is involved.

[20] The pharmaceutical composition according to paragraph [18] for use in the prophylaxis or treatment of Alzheimer's disease.

[21] An oral or parenteral preparation comprising the compound or its salt according to any one of [1] to [14] and one or more pharmacologically acceptable carriers.

[22] A compound represented by the following general formula (II):

[in which Ar ³ and Ar ⁴ are the same or different, and each denotes a homocyclic or heterocyclic group, optionally having a substituent

(except where (i) Ar ³ is an aryl or heteroaryl group, optionally having a substituent, and Ar ⁴ is a phenyl group, optionally having a substituent at position 2 and having an electron withdrawing group, 1H-indol-2-yl a group, if necessary, having a substituent, 1H-indol-3-yl group, if necessary, having a substituent, 1H-indol-4-yl group, if necessary, having a substituent, 1H-indol-5-yl group, if necessary having a substituent, 1H-indol-6-yl g a group, optionally having a substituent, or a 1H-indol-7-yl group, optionally having a substituent, and

where (ii) Ar ³ is a phenyl group, optionally substituted with a hydroxyl group, methoxy group or acetoxy group, and Ar ⁴ is a phenyl group, 4-chlorophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3 -hydroxyphenyl group, 4-acetylaminophenyl group, 3,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,3-dimethoxyphenyl group, 2,4-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,5-dimethoxyphenyl group , 3,4-dihydroxyphenyl group, 3-fluoro p-4-hydroxyphenyl group, 2-hydroxy-5-methoxyphenyl group, 3-hydroxy-4-methoxyphenyl group, 3-hydroxy-5-methoxyphenyl group, 3-methoxy-4-nitrophenyl group, 4-acetoxy-3-methoxyphenyl group, 4-dimethylamino-3-methoxyphenyl group, 4-hydroxy-3-nitrophenyl group, 2-methoxynaphthalen-1-yl group, 6-methoxynaphthalen-2-yl group, 1H-pyrrol-2-yl group, pyridin-2 -yl group, 1H-imidazol-2-yl group, 1-methyl-1H-pyrrol-2-yl group, 9-ethyl-9H-carbazol-3-yl group, 1-methyl-1H-indol-3-yl group, 1H-indol-3-yl group ny, 1H-indol-5-yl group or 1H-indol-6-yl group)]

or its salt.

Advantageous Effects of the Invention

The compound of the present invention has tau aggregation inhibitory activity, β-secretase inhibitory activity, Aβ aggregation inhibitory activity and the like, as well as high penetration into the brain, and thus can be used as a therapeutic agent for the treatment of Alzheimer's disease etc.

Brief Description of Drawings

FIG. 1 represents electron diffraction patterns of a sample of thioflavin S obtained in Pharmacological Testing Example 1. The left figure shows the result obtained in the case where only DMSO was added, the middle figure shows the result obtained in the case where the compound of Example 2 was added in an amount of 0.1 μM, and the right figure shows the result obtained in the case where the compound of Example 2 was added in an amount of 1 μM.

FIG. 2 is a diagram showing changes in blood concentration of the compounds of Example 2 and Example 2 (2) after their oral administration.

FIG. 3 is a graph showing the amounts of insoluble and soluble Aβ 1-42 in the brain of mice injected with the compound of Example 2. The left figure shows the amounts of insoluble Aβ 1-42, and the right figure shows the amounts of soluble Aβ 1-42.

FIG. 4 is a graph showing the amount of insoluble tau in the brain of mice injected with the compound of Example 2.

Description of Embodiments

The present invention will be described in detail below.

R in the general formula (I) is hydrogen having a chain or a cyclic hydrocarbon group, optionally having a substituent, or a heterocyclic group, optionally having a substituent, and is preferably hydrogen. A chain or cyclic hydrocarbon group is not particularly limited provided that it does not attenuate the effects of the present invention, and examples of this group include (preferably C _1-6 ) alkyl groups such as a methyl group, an ethyl group, a propyl group and an isopropyl group; (preferably C _1-6 ) alkenyl groups, such as a vinyl group; (preferably C _6-12 ) aryl groups such as a phenyl group and a naphthyl group; etc. The heterocyclic group is not particularly limited, provided that it does not attenuate the effects of the present invention. Examples of this group include heterocyclic groups containing 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom, and particular examples of this include a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a furyl group, a thienyl group, an oxazolyl group etc. A substituent is not particularly limited provided that it does not attenuate the effects of the present invention, and examples of this substituent include (preferably C _1-6 ) alkyl groups such as a methyl group and an ethyl group; (preferably C _7-10 ) aralkyl groups such as a benzyl group; (preferably C _2-7 ) acyl groups such as an acetyl group and a benzoyl group; (preferably C _2-7 ) alkylcarbonyl groups such as a tert-butoxycarbonyl group; (preferably C _1-6 ) alkylsulfonyl groups such as a methylsulfonyl group and a p-toluenesulfonyl group; hydroxyl group; nitro group; etc.

Ar ¹ and Ar ² in the general formula (I) are the same or different, and each of them represents a homocyclic or heterocyclic group, optionally having a substituent. A “homocyclic group” is not particularly limited provided that it does not weaken the effects of the present invention, and examples of this group include a vinyl group, a phenyl group, a naphthyl group, etc. A “heterocyclic group” is not particularly limited provided that it does not attenuate the effects of the present invention, and examples of this group include a pyrrolyl group, a pyrrolynyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a furyl group, a thienyl group, an oxazolyl group, etc. d. A “bicyclic homocyclic group” is not particularly limited provided that it does not attenuate the effects of the present invention, and examples of this group include a naphthyl group, etc. A substituent is not particularly limited provided that it does not attenuate the effects of the present invention, and examples of this substituent include (preferably C _1-6 ) alkyl groups such as a methyl group and an ethyl group; (preferably C _7-10 ) aralkyl groups such as a benzyl group; (preferably C _2-7 ) acyl groups such as an acetyl group and a benzoyl group; (preferably C _2-7 ) alkylcarbonyl groups such as a tert-butoxycarbonyl group; (preferably C _1-6 ) alkylsulfonyl groups such as a methylsulfonyl group and a p-toluenesulfonyl group; hydroxyl group; nitro group, etc.

Preferably, Ar ¹ represents a phenyl group, optionally having a substituent. The substituent on the phenyl group is not particularly limited, provided that it does not weaken the effects of the present invention, and preferred examples of this substituent include

(1) a C _1-3 alkyloxy group, optionally having a substituent,

(2) an aryloxy group, optionally having a substituent,

(3) a disubstituted amino group (in which these two substituents can together form a ring),

(4) an aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent,

(5) a bromine atom,

(6) an alkyl group, optionally having a substituent, an alkenyl group, optionally having a substituent, or an alkynyl group, optionally having a substituent,

(7) a nitro group,

(8) an acyl group,

(9) an alkylcarbonylamino group, a sulfonyl group, a sulfinyl group or a sulfonyloxy group, etc.

(1) a C _1-3 alkyloxy group, optionally having a substituent

Examples of the “C _1-3 alkyloxy group optionally having a substituent” include

(1a) a C _1-3 alkyloxy group substituted with a heterocycloalkyl group, optionally having a substituent,

(1b) a C _1-3 alkyloxy group substituted with a cycloalkyl group, optionally having a substituent,

(1c) a C _1-3 alkyloxy group substituted with a heteroaryl group, optionally having a substituent,

(1d) a C _1-3 alkyloxy group substituted with an aryl group, optionally having a substituent,

(1e) a C _1-3 alkyloxy group substituted with a dialkylamino group, optionally having a substituent,

(1f) a C _1-3 alkyloxy group substituted with an alkyloxy group, optionally having a substituent,

(1g) a C _1-3 alkyloxy group substituted with an alkyl group, optionally having a substituent, etc.

(1a) a C _1-3 alkyloxy group substituted with a heterocycloalkyl group, optionally having a substituent

Examples of the “C _1-3 alkyloxy group substituted with a heterocycloalkyl group optionally having a substituent” include tetrahydrofuran-3-ylmethoxy group, tetrahydrofuran-2-ylmethoxy group, 2- (piperidin-1-yl) ethoxy group, 2- (4-methylpiperazino) ethoxy , 2- (4-benzylpiperazino) ethoxy group, 2-morpholinoethoxy group, 2-pyrrolidinoethoxy group, β-D-glucopyranosyloxy group, 2- [4- (tert-butoxycarbonyl) piperazin-1-yl] ethoxy group, 2- [4- (methyl) piperazin-1-yl] ethoxy group, 2- [4- (2-hydroxyethyl) piperazin-1-yl] ethoxy group, etc.

Examples of a “phenyl group having a C _1-3 alkyloxy group substituted with a heterocycloalkyl group, optionally having a substituent” include a 2-methoxy-4- (tetrahydrofuran-3-ylmethoxy) phenyl group, 2-methoxy-4- (tetrahydrofuran-2- ylmethoxy) phenyl group, 2-methoxy-4- [2- (piperidin-1-yl) ethoxy] phenyl group, 2-methoxy-4- [2- (4-methylpiperazino) ethoxy] phenyl group, 2-methoxy-4 - (2-morpholinoethoxy) phenyl group, 4- (β-D-glucopyranosyl) hydroxy-2-methoxyphenyl group, 4- (tetrahydrofuran-3-ylmethoxy) phenyl group, 4- (tetrahydrofuran-2-yl ethoxy) phenyl group, 3-methoxy-4- (tetrahydrofuran-3-ylmethoxy) phenyl group, 3-methoxy-4- (tetrahydrofuran-2-ylmethoxy) phenyl group, 2- [2- (4-benzylpiperazino) ethoxy] - 4-methoxyphenyl group, 4-diethylamino-2- (2-morpholinoethoxy) phenyl group, 4-dimethylamino-2- (2-morpholinoethoxy) phenyl group, 4-diethylamino-2- (2-morpholinoethoxy) phenyl group, 4-diethylamino A -2- (2-pyrrolidinoethoxy) phenyl group, 4-diethylamino-2- [2- (piperidin-1-yl) ethoxy] phenyl group, etc.

(1b) a C _1-3 alkyloxy group substituted with a cycloalkyl group, optionally having a substituent

Examples of the “C _1-3 alkyloxy group substituted with a cycloalkyl group, optionally having a substituent” include cyclohexylmethoxy group, etc.

Examples of the “phenyl group having a C _1-3 alkyloxy group substituted with a cycloalkyl group, optionally having a substituent” include a 4-cyclohexylmethoxy-2-methoxyphenyl group, a 2-cyclohexylmethoxy-4-hydroxyphenyl group, a 2-cyclohexylmethoxy-3-fluorophenyl group, 2-cyclohexylmethoxy-5-fluorophenyl group, 5-chloro-2-cyclohexylmethoxyphenyl group, 2,4-di (cyclohexylmethoxy) phenyl group, etc.

(1c) a C _1-3 alkyloxy group substituted with a heteroaryl group optionally having a substituent

Examples of the “C _1-3 alkyloxy group substituted with a heteroaryl group optionally having a substituent” include pyridin-2-ylmethoxy group, pyridin-3-ylmethoxy group, pyridin-4-ylmethoxy group, 1-pyrrolylmethoxy group, etc.

Examples of the “phenyl group having a C _1-3 alkyloxy group substituted with a heteroaryl group, optionally having a substituent” include 4- (pyridin-2-ylmethoxy) phenyl group, 2-methoxy-4- (pyridin-2-ylmethoxy) phenyl group , 2- [2- (piperidin-1-yl) ethoxy] -4- (pyridin-2-ylmethoxy) phenyl group, 2- (2-morpholinoethoxy) -4- (pyridin-2-ylmethoxy) phenyl group, 2- (2-pyrrolidinoethoxy) -4- (pyridin-2-ylmethoxy) phenyl group, 2- [2- (4-methylpiperazino) ethoxy] -4- (pyridin-2-ylmethoxy) phenyl group, 3-methoxy-4- ( pyridin-2-ylmethoxy) phenyl group, 2-hydro si-4- (pyridin-2-ylmethoxy) phenyl group, 3- (pyridin-2-ylmethoxy) phenyl group, 2-methoxy-3- (pyridin-2-ylmethoxy) phenyl group, 4-methoxy-3- (pyridine -2-ylmethoxy) phenyl group, 3-methoxy-5- (pyridin-2-ylmethoxy) phenyl group, 2-methoxy-5- (pyridin-2-ylmethoxy) phenyl group, 2- (pyridin-2-ylmethoxy) phenyl group, 4-methoxy-2- (pyridin-2-ylmethoxy) phenyl group, 5-methoxy-2- (pyridin-2-ylmethoxy) phenyl group, 2-nitro-5- (pyridin-3-ylmethoxy) phenyl group, 4-diethylamino-2- (pyridin-3-ylmethoxy) phenyl group, 2-methoxy-2- (1-pyrrolylmethoxy) phenyl group, etc.

(1d) a C _1-3 alkyloxy group substituted with an aryl group optionally having a substituent

Examples of the “C _1-3 alkyloxy group substituted with an aryl group, optionally having a substituent” include a phenethyloxy group, a benzyloxy group, a 1-naphthylmethoxy group, a diphenylmethoxy group, 4-methoxybenzyloxy group, 2-chloro-6-fluorobenzyloxy group, 2,4-dichlorobenzyl 4-dichlorobenzyl 4-dichlorobenzyl -butylbenzyloxy group, etc.

Examples of a “phenyl group having a C _1-3 alkyloxy group substituted with an aryl group optionally having a substituent” include a 2-methoxy-4-phenethyloxyphenyl group, a 4-benzyloxy-2-methoxyphenyl group, 4- (1-naphthylmethoxy) -2 -methoxyphenyl group, 4-diphenylmethoxy-2-methoxyphenyl group, 2-benzyloxy-4-hydroxyphenyl group, 2-benzyloxy-4-chlorophenyl group, 2-benzyloxy-3-fluorophenyl group, 2-benzyloxy-3,5-dichlorophenyl group 5-benzyloxy-2-nitrophenyl group, 5- (4-methoxybenzyloxy) -2-nitrophenyl group, 5 - (2-chloro-6-fluorobenzyloxy) -2-nitrophenyl group, 5- (2,4-dichlorobenzyloxy) -2-nitrophenyl group, 5- (4-tert-butylbenzyloxy) -2-nitrophenyl group, 4-benzyloxy- 2-bromophenyl group, 4-benzyloxy-2-phenylphenyl group, 2-benzyloxy-5-bromophenyl group, 2-benzyloxy-5-phenylphenyl group, 2-benzyloxy-5- (indol-6-yl) phenyl group, 2- benzyloxy-4-dimethylaminophenyl group, 2-benzyloxy-4-diethylaminophenyl group, 4-diethylamino-2- (4-methoxybenzyloxy) phenyl group, 4-diethylamino-2- (2-chloro-6-fluorobenzyloxy) phenyl group, 4- diethylamino 2- (2,4-dichlorobenzyloxy) phenyl group, 4-diethylamino-2- (4-tert-butylbenzyloxy) phenyl group, etc.

(1e) a C _1-3 alkyloxy group substituted with a dialkylamino group optionally having a substituent

Examples of the “C _1-3 alkyloxy group substituted with a dialkylamino group optionally having a substituent” include a 2-dimethylaminoethoxy group, 3-dimethylaminopropoxy group, 2-dimethylamino-1-methylethoxy group, 2-dimethylamino-1-methylethoxy group, etc.

Examples of the “phenyl group having a C _1-3 alkyloxy group substituted with a dialkylamino group, optionally having a substituent” include 4- (3-dimethylaminopropoxy) phenyl group, 2-chloro-4- (3-dimethylaminoethoxy) phenyl group, 2-bromo- 5- (3-dimethylaminoethoxy) phenyl group, 2- (2-dimethylaminoethoxy) -4-methoxyphenyl group, 4-diethylamino-2- (2-dimethylamino-1-methylethoxy) phenyl group, etc.

(1f) a C _1-3 alkyloxy group substituted with an alkyloxy group, optionally having a substituent

Examples of the “C _1-3 alkyloxy group substituted with an alkyloxy group optionally having a substituent” include a methoxyethoxy group, a benzyloxyethoxy group, etc.

Examples of the “phenyl group having a C _1-3 alkyloxy group substituted with an alkyloxy group, optionally having a substituent” include a 2-methoxy-4-methoxyethoxyphenyl group, a 2-benzyloxyethoxy-4-methoxyphenyl group, etc.

(1g) C _1-3 alkyloxy group substituted with an alkyl group optionally having a substituent

Examples of the “C _1-3 alkyloxy group substituted by an alkyl group optionally having a substituent” include an isopropoxy group, a 2-methylpropoxy group, a 3-methyl-2-butenyloxy group, etc.

Examples of the “phenyl group having a C _1-3 alkyloxy group substituted with an alkyl group, optionally having a substituent” include a 4-hydroxy-2-isopropoxyphenyl group, a 4-isopropoxy-2-methoxyphenyl group, 2-methoxy-4- (2- methylpropoxy) phenyl group, 3-fluoro-2- (2-methylpropoxy) phenyl group, 2,5-di (2-methylpropoxy) phenyl group, 2,4-di (2-methylpropoxy) phenyl group, 4-diethylamino-2 -isopropoxyphenyl group, 4-diethylamino-2- (3-methyl-2-butenyloxy) phenyl group, etc.

(2) Aryloxy group, optionally having a substituent

Examples of the “aryloxy group optionally having a substituent” include a phenoxy group, etc.

Examples of a “phenyl group having an aryloxy group, optionally having a substituent” include a 2-phenoxyphenyl group, a 3-phenoxyphenyl group, a 4-phenoxyphenyl group, etc.

(3) Disubstituted amino group

Examples of the “disubstituted amino group” include dimethylamino group, diethylamino group, etc. Examples of the “disubstituted amino group” in which the two substituents form a ring together include an imidazol-1-yl group, a pyrazol-1-yl group, a triazol-2-yl group, a pyrrolidin-1-yl group, and piperidin-1-yl group , 4-benzylpiperidin-1-yl group, morpholin-4-yl group, piperazin-1-yl group, 4-methylpiperazin-1-yl group, 4-benzylpiperazin-1-yl group, 4-phenylpiperazin-1-yl group 4- (tert-butoxycarbonyl) piperazin-1-yl group, 4- (methylsulphonyl) piperazin-1-yl group, 4- (2-hydroxyethyl) piperazin-1-yl group pu, 1,4-diazepan-1-yl group, 4-methyl-1,4-diazepan-1-yl group, 4-benzyl-1,4-diazepan-1-yl group, 4- (tert-butoxycarbonyl) -1,4-diazepan-1-ilen group, etc.

Examples of the “phenyl group having a disubstituted amino group (in which two substituents can form a ring together)” include a 4-dimethylaminophenyl group, 4-dimethylamino-2-methoxyphenyl group, 4-diethylamino-2-hydroxyphenyl group, 4-diethylamino-2-methoxyphenyl group, 2-dimethylaminophenyl group, 4-bromo-2-dimethylaminophenyl group, 5-bromo-2-dimethylaminophenyl group, 2-dimethylamino-5-trifluoromethylphenyl group, 2-dimethylamino-4-phenylphenyl group, 2-dimethylamino-5-phenyl group, 4-dimethylamino-3-metho syphenyl group, 4-dimethylamino-2-nitrophenyl group, 4-dimethylamino-2-chlorophenyl group, 4-dimethylamino-2-methoxymethoxyphenyl group, 4-dimethylamino-2-trifluoromethylphenyl group, 5-dimethylamino-2-nitrophenyl group, 2- benzoyloxy-4-diethylaminophenyl group, 4-diethylamino-2-ethoxycarbonyloxyphenyl group, 4-diethylamino-2-ethylaminocarbonyloxyphenyl group, 4-diethylamino-2- (2-hydroxyethoxy) phenyl group, 4- (imidazol-1-yl) phenyl group 4- (pyrazol-1-yl) phenyl group, 4- (triazol-2-yl) phenyl group, 4- (pyrrolidin- 1-yl) phenyl group, 4- (piperidin-1-yl) phenyl group, 4- (morpholin-4-yl) phenyl group, 4- (piperazin-1-yl) phenyl group, 4- (4-methylpiperazin- 1-yl) phenyl group, 4- (4-benzylpiperazin-1-yl) phenyl group, 2- (pyrrolidin-1-yl) phenyl group, 2- (piperidin-1-yl) phenyl group, 2- (morpholin- 4-yl) phenyl group, 2- [4- (tert-butoxycarbonyl) piperazin-1-yl] phenyl group, 2- [4- (methylsulfonyl) piperazin-1-yl] phenyl group, 2- [4- (2 -hydroxyethyl) piperazin-1-yl] phenyl group, 2-bromo-4- (piperidin-1-yl) phenyl group, 2-bromo-4- (4-benzylpiperidin-1-yl) phenyl g uppu, 2-bromo-4- (morpholin-4-yl) phenyl group, 2-bromo-4- (4-methylpiperazin-1-yl) phenyl group, 2-bromo-4- (4-benzylpiperazin-1-yl ) phenyl group, 2-bromo-4- (4-phenylpiperazin-1-yl) phenyl group, 2-bromo-4- (pyrrolidin-1-yl) phenyl group, 2-bromo-4- [4- (tert- butoxycarbonyl) piperazin-1-yl] phenyl group, 2-bromo-4- (piperazin-1-yl) phenyl group, 2-bromo-4- [4- (methylsulfonyl) piperazin-1-yl] phenyl group, 2- bromo-4- [4- (2-hydroxyethyl) piperazin-1-yl] phenyl group, 4- (1,4-diazepan-1-yl) phenyl group, 4- (4-methyl-1,4-diazepan- 1-yl) phenyl group, 4- (4-benzyl-1,4-diazepan-1-yl) f phenyl group, 4- [4- (tert-butoxycarbonyl) -1,4-diazepan-1-yl] phenyl group, 2-bromo-4- (1,4-diazepan-1-yl) phenyl group, 2-bromo -4- (4-methyl-1,4-diazepan-1-yl) phenyl group, 2-bromo-4- (4-benzyl-1,4-diazepan-1-yl) phenyl group, 2-bromo-4 - [4- (tert-butoxycarbonyl) -1,4-diazepan-1-yl] phenyl group, 5-hydroxy-2- (pyrrolidin-1-yl) phenyl group, 5-hydroxy-2- (piperidin-1- il) phenyl group, 5-hydroxy-2- (morpholin-4-yl) phenyl group, 2- (4-benzylpiperidin-1-yl) -5-hydroxyphenyl group, 5-hydroxy-2- [4- (2- hydroxyethyl) piperazin-1-yl] phenyl group, 5-hydroxy-2- (piperazin -1-yl) phenyl group, 2- [4- (tert-butoxycarbonyl) piperazin-1-yl] -5-hydroxyphenyl group, 5-hydroxy-2- (4-phenylpiperazin-1-yl) phenyl group, 5- hydroxy-2- (4-methylpiperazin-1-yl) phenyl group, 2- (1,4-diazepan-1-yl) -5-hydroxyphenyl group, 5-hydroxyphenyl-2- (4-methyl-1,4- diazepan-1-yl) group, 2- (4-benzyl-1,4-diazepan-1-yl) -5-hydroxyphenyl group, 2- [4- (tert-butoxycarbonyl) -1,4-diazepan-1- yl] -5-hydroxyphenyl group, 5-bromo-2- [4- (2-hydroxyethyl) piperazin-1-yl] phenyl group, etc.

(4) An aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent

Examples of the “aryl group optionally having a substituent” include a phenyl group, a 2-methylphenyl group, a 2-ethoxyphenyl group, a 1-naphthyl group, a 2-naphthyl group, etc. Examples of a “heteroaryl group optionally substituted” include a 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, imidazol-1-yl group, 1H-1,2,4-triazol-1-yl group, 4 -ethoxycarbonyl-1H-1,2,3-triazol-1-yl group, 5-ethoxycarbonyl-1H-1,2,3-triazol-1-yl group, 1-benzyl-1H-1,2,3-triazole -4-yl group, 1-benzyl-1H-1,2,3-triazol-5-yl group, 1-ethoxycarbonylmethyl-1H-1,2,3-triazol-4-yl group, 1-ethoxycarbonylmethyl-1H- 1,2,3-triazol-5-yl group, 1H-benzimidazol-1-yl group, 1H-tetrazol-5-yl group, 1-benzyl-1H-tet split-5-yl group, 1-ethoxycarbonylmethyl-1H-tetrazol-5-yl group, etc.

Examples of the “phenyl group having an aryl group, optionally having a substituent, or the phenyl group having a heteroaryl group, optionally having a substituent” include a 2-phenylphenyl group, 3-phenylphenyl group, 4-phenylphenyl group, 5-hydroxy-2 -phenylphenyl group, 5-fluoro-2-phenylphenyl group, 5-chloro-2-phenylphenyl group, 5-hydroxy-2- (2-methylphenyl) phenyl group, 2- (2-ethoxyphenyl) -5-hydroxyphenyl group, 2 - (1-naphthyl) phenyl group, 2- (2-naphthyl) phenyl group, 5-hydroxy-2- (1 naphthyl) phenyl th group, 2- (2-pyridyl) phenyl group, 2- (3-pyridyl) phenyl group, 2- (4-pyridyl) phenyl group, 4- (2-pyridyl) phenyl group, 4- (imidazole-1- il) phenyl group, 4- (1H-benzimidazol-1-yl) phenyl group, 2- (1H-1,2,4-triazol-1-yl) phenyl group, 2- (4-ethoxycarbonyl-1H-1, 2,3-triazol-1-yl) phenyl group, 2- (5-ethoxycarbonyl-1H-1,2,3-triazol-1-yl) phenyl group, 2- (1-benzyl-1H-1,2, 3-triazol-4-yl) phenyl group, 2- (1-benzyl-1H-1,2,3-triazol-5-yl) phenyl group, 2- (1-ethoxycarbonylmethyl-1H-1,2,3- triazol-4-yl) phenyl group, 2- (1-ethoxycarbonylmethyl-1H-1,2,3-triazol-5-yl) phenyl group y, 2- (1H-tetrazol-5-yl) phenyl group, 2- (1-benzyl-1H-tetrazol-5-yl) phenyl group, 2- (1-ethoxycarbonylmethyl-1H-tetrazol-5-yl) phenyl group etc.

(5) Bromine atom

Examples of the “phenyl group having a bromine atom” include a 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-bromo-3-hydroxyphenyl group, 2-bromo-4-hydroxyphenyl group, 2-bromo-5-hydroxyphenyl group, 2-bromo-5-methoxyphenyl group, 2-bromo-5-methoxymethoxyphenyl group, 4-bromo-2-fluorophenyl group, 5-bromo-2-fluorophenyl group, 2-bromo-4-hydroxy-5-methoxyphenyl group , 2-bromo-5-hydroxy-4-methoxyphenyl group, 2,4-dibromo-5-hydroxyphenyl group, 2,3-dibromo-4-hydroxy-5-methoxyphenyl group, etc.

(6) An alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, or an alkynyl group optionally having a substituent

Examples of an “alkyl group, optionally having a substituent, an alkenyl group, optionally having a substituent, or an alkynyl group, optionally having a substituent” include an isopropyl group, a hydroxymethyl group, an n-propyl group, a 2-cyclopropylethyl group, 2- ( methoxymethyl) ethyl group, 2- (dimethylaminomethyl) ethyl group, 2- (diethylaminomethyl) ethyl group, phenethyl group, 2- (pyridin-2-yl) ethyl group, 2- (pyridin-3-yl) ethyl group, 2- (pyridin-4-yl) ethyl group, 2-methylene an alkyl group, a 2-cyclopropylethylene group, a 2- (methoxymethyl) ethenyl group, a 2- (dimethylaminomethyl) ethenyl group, a 2- (diethylaminomethyl) ethenyl group, a styryl group, a 2- (pyridin-2-yl) ethenyl group, 2- ( pyridin-3-yl) ethenyl group, 2- (pyridin-4-yl) ethenyl group, 1-propynyl group, cyclopropylethynyl group, methoxymethylethynyl group, 2- (dimethylaminomethyl) ethynyl group, 2- (diethylaminomethyl) ethynyl group, phenylethynyl group , pyridin-2-yl-ethynyl group, pyridin-3-yl-ethynyl group, pyridin-4-yl-ethynyl hydrochloric group, etc.

Examples of “a phenyl group having an alkyl group, optionally having a substituent, a phenyl group having an alkenyl group, optionally having a substituent, or a phenyl group having an alkynyl group, optionally having a substituent” include 4-isopropylphenyl group, 2- (hydroxymethyl) phenyl group, 2-methoxy-4- (n-propyl) phenyl group, 4- (2-cyclopropylethyl) -2-methoxyphenyl group, 2-methoxy-4- [2- (methoxymethyl) ethyl] phenyl group, 4- [2- (dimethylaminomethyl) ethyl] -2-methoxyphenyl group , 4- [2- (diethylaminomethyl) ethyl] -2-methoxyphenyl group, 2-methoxy-4-phenethylphenyl group, 2-methoxy-4- [2- (pyridin-2-yl) ethyl] phenyl group, 2-methoxy -4- [2- (pyridin-3-yl) ethyl] phenyl group, 2-methoxy-4- [2- (pyridin-4-yl) ethyl] phenyl group, 2-styrylphenyl group, 2-methoxy-4- (2-Methylenethenyl) phenyl group, 4- (2-cyclopropylethenyl) -2-methoxyphenyl group, 2-methoxy-4- [2- (methoxymethyl) ethenyl] phenyl group, 4- [2- (dimethylaminomethyl) ethenyl] -2 -methoxyphenyl group, 4- [2- (diethylaminomethyl) ethenyl] -2-methoxyphenyl group, 2-methoxy-4-styrylphenyl group pu, 2-methoxy-4- [2- (pyridin-2-yl) ethenyl] phenyl group, 2-methoxy-4- [2- (pyridin-3-yl) ethenyl] phenyl group, 2-methoxy-4- [2- (pyridin-4-yl) ethenyl] phenyl group, 2-methoxy-4- (1-propynyl) phenyl group, 4- (2-cyclopropylethynyl) -2-methoxyphenyl group, 2-methoxy-4- [2 - (methoxymethyl) ethynyl] phenyl group, 4- [2- (dimethylaminomethyl) ethynyl] -2-methoxyphenyl group, 4- [2- (diethylaminomethyl) ethynyl] -2-methoxyphenyl group, 2-methoxy-4- (phenylethinyl) phenyl group, 2-methoxy-4- [2- (pyridin-2-yl) ethynyl] phenyl group, 2-methoxy-4- [2- (pyridin-3-yl) ethynyl] phenyl group, 2 -methoxy-4- [2- (pyridin-4-yl) ethynyl] phenyl group, etc.

(7) Nitro group

Examples of the “phenyl group having a nitro group” include a 2-nitrophenyl group, a 4-hydroxy-3-nitrophenyl group, a 3-methoxy-4-nitrophenyl group, a 5-methoxy-2-nitrophenyl group, a 5-methoxymethoxy-2-nitrophenyl group, 5-fluoro-2-nitrophenyl group, 5-hydroxy-2-nitrophenyl group, 5-chloro-2-nitrophenyl group, 2-chloro-5-nitrophenyl group, 4,5-dimethoxy-2-nitrophenyl group, etc. .

(8) Acyl group

Examples of the “phenyl group having an acyl group” include a 2-hydroxycarbonylphenyl group, a 3-hydroxycarbonylphenyl group, a 2-methoxycarbonylphenyl group, a 3-methoxycarbonylphenyl group, a 4-methoxycarbonylphenyl group, a 2-dimethylaminocarbonylphenyl group, and 3- (di-phenyl-n-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-carbonyl-phenyl-phenyl) -phenyl-phenyl-carbonyl-phenyl-phenyl-group). group etc.

(9) Alkylcarbonylamino group and other groups

A “phenyl group, optionally having a substituent” also includes a phenyl group having an alkylcarbonylamino group, a sulfonyl group, a sulfinyl group, or a sulfonyloxy group.

The number of substituents (1) to (9) introduced into the phenyl group is not particularly limited, and many identical or different substituents may be present. Preferably, the number of substituents introduced into the phenyl group is only one. The position of the substituents (1) to (9) on the phenyl group is also not particularly limited, and the substituents can be present in the ortho, meta and / or para position. Preferably, the substituent is introduced into the para position. The phenyl group represented by Ar ¹ may have a substituent not included in the aforementioned substituents (1) to (9), namely, a hydroxyl group, a methoxy group and a halogen atom other than a bromine atom, etc.

Ar ² in the general formula (I) preferably denotes a homocyclic or heterocyclic group, optionally having a substituent, more preferably a bicyclic homocyclic or heterocyclic group, optionally having a substituent, most preferably a bicyclic heterocyclic group, optionally having a substituent.

The “bicyclic heterocyclic group” is not particularly limited, provided that it does not attenuate the effects of the present invention. Preferred examples of this group include an indol-2-yl group, indol-3-yl group, indol-4-yl group, indol-5-yl group, indol-6-yl group, indol-7-yl group, benzotriazol-5 -yl group, benzimidazol-5-yl group, quinoxaline-6-yl group, benzofuran-2-yl group, benzothiophen-2-yl group, 1H-indazol-5-yl group, 7-azaindole-3-yl group, quinolin-2-yl group, quinolin-5-yl group, quinolin-8-yl group, 1,4-benzodioxan-6-yl group, 1,3-benzodioxol-5-yl group, chromon-3-yl group, coumarin-6-ylnu group, 7-methoxycoumarin-4-yl group, a 4-methoxycoumarin-6-yl group, etc. Examples of a substituent on a bicyclic heterocyclic group include a methyl group, an ethyl group, a benzyl group, an acetyl group, a benzoyl group, a tert-butoxycarbonyl group, a methylsulfonyl group, a p-toluenesulfonyl group, a hydroxyl group, a nitro group, etc.

The “bicyclic heterocyclic group optionally having a substituent” is not particularly limited, provided that it does not attenuate the effects of the present invention. Preferred examples of this group include an unsubstituted bicyclic heterocyclic group; 1-methyl-indol-6-yl group, 1-methylindol-2-yl group, 1-methylindol-3-yl group, 1-ethylindol-6-yl group, 1-benzylindol-3-yl group, 1-benzylindole -6-yl group, 1-acetylindol-3-yl group, 1-acetylindol-6-yl group, 1-benzoylindol-3-yl group, 1-tert-butoxycarbonylindol-5-yl group, 1-methylsulfonylindol-3- a methyl group, a 1-methylsulfonylindol-6-yl group, a 1-p-toluenesulfonylindol-3-yl group, a 1-p-toluenesulfonylindol-6-yl group, a 4-hydroxyindol-3-yl group, 4-nitroindol-3-yl group, etc .; a bicyclic heterocyclic group substituted with an alkyl group (e.g., a C _1-6 alkyl group), an aralkyl group (e.g., a C _7-10 aralkyl group), an acyl group (e.g., a C _2-10 acyl group), a hydroxyl group, a nitro group or the like ; etc.

In view of the inhibitory activity against aggregation of tau, etc., the preferred structure of the compound represented by general formula (I) is as follows.

Ar ¹ in the general formula (I) is particularly preferably a phenyl group having the aforementioned substituent (1), more preferably a phenyl group having the aforementioned substituent (1a) or (1c), even more preferably 2-methoxy-4- (pyridin-2 -ylmethoxy) phenyl group.

Ar ² in general formula (I) is particularly preferably an indol-2-yl group, optionally having a substituent, indol-3-yl group, optionally having a substituent, indol-4-yl group, optionally having a substituent, an indol-5-yl group, optionally having a substituent, an indol-6-yl group, optionally having a substituent, an indol-7-yl group, optionally having a substituent, a benzotriazol-5-yl group, optionally having Deputy, benzimidazole- 5-yl group, if necessary having a substituent, quinoxalin-6-yl group, if necessary, having a substituent, benzofuran-2-yl group, if necessary, having a substituent, or benzothiophen-2-yl group, if necessary, having a substituent ; more preferably indol-2-yl group, indol-3-yl group, indol-6-yl group, 1-methyl-indol-6-yl group, benzotriazol-5-yl group, benzimidazol-5-yl group, quinoxaline A 6-yl group, a benzofuran-2-yl group or a benzothiophen-2-yl group; even more preferably, an indol-6-yl group.

The salt of the compound represented by general formula (I) is also encompassed in the present invention. The salt is preferably a pharmacologically acceptable salt, and examples of this salt include hydrohalic acid salts such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic acid salts such as sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate; organic carboxylic acid salts such as acetate, oxalate, maleate, tartrate and fumarate; organic sulfonic acid salts such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and camphorsulfonate; amino acid salts such as aspartate and glutamate; amine salts such as trimethylamine salt, triethylamine salt, procaine salt, pyridine salt and phenethylbenzylamine salt; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; etc. Hydrochloride and oxalate are preferred.

A compound represented by general formula (I) can be prepared using the method described in, for example, Rajeshwar Narlawar et al., ChemMedChem 2008, 3, 165-172, WO2008 / 066151, WO2009 / 145219 and the like, or any combination of the methods described in these literary sources. In particular, the compound can be obtained by the following Steps 1 and 2.

In the above formula, Ar ¹ and Ar ² are as defined above.

In Step 1, the aldehyde represented by the general formula (A) is allowed to react with the compound represented by the general formula (B) in the presence of a solvent and a catalyst, to obtain a diketone represented by the general formula (C). This diketone represented by the general formula (C) or a salt thereof is also encompassed in the present invention. In the above formula, the aldehyde represented by the general formula (A) has Ar ¹ and the compound represented by the general formula (B) has Ar ² . However, the aldehyde corresponding to the aldehyde of general formula (A) may have Ar ² , and the compound corresponding to the compound of general formula (B) may have Ar ¹ , and the diketone of general formula (C) can be obtained by reacting an aldehyde having Ar ² , and a compound having Ar ¹ .

The solvent used in the reaction is not particularly limited provided that it does not inhibit the reaction, and examples of this solvent include ethyl acetate, N, N-dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, etc. d. These solvents can be used individually or in combination of two or more kinds of these solvents in a suitable mixing ratio.

The catalyst used in the reaction is also not particularly limited. Examples of this catalyst include bases such as a primary amine and a secondary amine, and particular examples include n-butylamine, ethanolamine, piperidine, morpholine, etc.

A water absorber may be added to absorb water generated in the reaction. Examples of a water scavenger include alkyl borate, alkyl phosphate, ortho ether, etc., and particular examples of this include trimethyl orthoformate and tri-n-butyl borate.

The proportion of the aldehyde represented by the general formula (A) and the compound represented by the general formula (B) is not particularly limited, but preferably the amount of the compound used is from 0.5 to 10 mol, more preferably from 0.5 to 2 mol, relative to 1 mole of aldehyde.

The reaction temperature is not particularly limited, but is preferably 0 to 200 ° C, more preferably 50 to 100 ° C.

The duration of the reaction is not particularly limited, but is preferably from 0.5 to 48 hours, more preferably from 1 to 24 hours.

The aldehyde represented by the general formula (A) and the compound represented by the general formula (B), which are used in step 1, may be commercially available products or synthesized in a known manner (for example, by the method described in WO2008 / 066151 or WO2009 / 145219).

In step 2, the diketone represented by the general formula (C) is allowed to react with hydrazine or a derivative thereof in the presence of a solvent to obtain a compound represented by the general formula (I). Depending on the target compound, Step 2 may have the step of adding a substituent to the compound of general formula (C) obtained by reacting a diketone with hydrazine or a derivative thereof (a compound represented by H ₂ N-NHR, a salt thereof or the like).

The hydrazine used in the reaction is not particularly limited, and examples of this include hydrazine monohydrate, an aqueous solution of hydrazine, anhydrous hydrazine, hydrazine acetate, hydrazine monohydrochloride, a derivative thereof, etc.

The solvent used in the reaction is not particularly limited provided that it does not inhibit the reaction, and examples of this solvent include protic solvents such as acetic acid, methanol, ethanol and water; non-protic solvents such as ethyl acetate, toluene, tetrahydrofuran, methylene chloride, chloroform, etc. These solvents can be used individually or in combination of two or more kinds of these solvents in a suitable mixing ratio.

The proportion of diketone represented by the general formula (C) to hydrazine is not particularly limited, but preferably the amount of hydrazine used is from 1 to 50 mol, more preferably from 2 to 10 mol, relative to 1 mol of diketone.

The reaction temperature is not particularly limited, but is preferably 20 to 120 ° C, more preferably 50 to 80 ° C.

The duration of the reaction is not particularly limited, but is preferably from 1 to 24 hours, more preferably from 1 to 6 hours.

The compounds of the present invention may be administered individually or in combination with one or more compounds of the present invention or with one or more compounds other than the compounds of the present invention. The compound of the present invention may be administered in the form of a composition comprising one or more pharmacologically acceptable carriers. The effective dosage and frequency of administration may vary depending on the dosage form, age, body weight, symptoms, etc. patient, etc., but the daily dosage is usually from about 0.01 to 100 mg / kg, more preferably from about 1 to 50 mg / kg.

A dosage form of an agent comprising a compound of the present invention as an active ingredient is not particularly limited, and this agent can be administered orally or parenterally in a conventional manner. The compound can be formulated and administered in the form of oral or parenteral preparations, such as tablets, powders, granules, capsules, solutions, emulsions, elixirs, suspensions, syrups, troches, inhalations, suppositories, injections, ointments, eye ointments, ophthalmic preparations, nasal preparations, ear preparations, cataplasma patches / gel, lotions, etc. The dosage of the drug according to the present invention can be determined as appropriate depending on the severity of the symptom, age, gender, body weight of the patient, dosage form, type of salt, specific disease, etc.

Since the compound of the present invention has tau aggregation inhibitory activity, β-secretase inhibitory activity, and Aβ aggregation inhibitory activity, the compound of the present invention is effective in the prevention and treatment of diseases in which tau, β-secretase or Aβ, such as Alzheimer's disease (familial Alzheimer's disease and sporadic Alzheimer's disease), senile dementia, Down syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis, etc. Among these nervous diseases, the compound of the present invention is particularly effective in the prevention and treatment of Alzheimer's disease.

The compound of the present invention may be formulated in a manner commonly used in a dosage form, such as a tablet, powder, fine granule, granule, coated tablet, capsule, solution, emulsion, elixir, suspension, syrup, lozenge, inhalation, suppository, injection, ointment, ophthalmic ointment, ophthalmic preparation, nasal preparation, ear preparation, cataplasma patch / gel, lotion, etc. To formulate in such a dosage form, an excipient, a binder, a lubricant, a colorant and an aroma modifier, which are commonly used to formulate a medicine, can be used, and if necessary, a stabilizer, emulsifier, absorption enhancer, surfactant, pH regulator, preservative, antioxidant and / or the like. Thus, ingredients that are commonly used as raw materials of a pharmaceutical composition can be mixed with the compound and formulated in the usual manner. For example, in the preparation of an oral preparation, a crystalline or amorphous compound according to the present invention is mixed with an excipient and, if necessary, with a binder, disintegrator, lubricant, dye, flavor modifier, etc. and form into a powder, a fine granule, granule, tablet, coated tablet, capsule, etc. in the usual way. Examples of the ingredient include animal and vegetable fats and oils, such as soybean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and paraffin wax; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols, such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as a fatty acid ester of polyoxyethylene, a fatty acid ester of sorbitan, a fatty acid ester of glycerol, a fatty acid ester of sorbitan polyoxyethylene, a cured polyoxyethylene castor oil and a block copolymer of polyoxyethylene-polyoxypropylene; water soluble polymers such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, polyacrylate, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyalcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, aluminum-magnesium silicate and aluminum silicate; purified water; etc. Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, etc. Examples of a binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, block polymer polypropylene glycol polyoxyethylene etc. Examples of the disintegrant include starch, agar-agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, calcium carboxyl methyl cellulose, etc. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silicon dioxide, hydrogenated vegetable oil, etc. Examples of the colorant include a colorant tested as a drug additive, etc. Examples of the flavor modifier include cocoa powder, menthol, aromatic powder, peppermint oil, borneol, cinnamon powder, etc. It goes without saying that the obtained tablets and granules can be coated with sugar or the like, if necessary. In preparing a solution, such as a syrup, emulsion, elixir, suspension and injection, the compound of the present invention is mixed, if necessary, with a pH regulator, a fluidizing agent, an emulsifier, a dispersing agent, an isotonic agent, a solubilizing agent, a stabilizer or the like, and formulated in such a solution in the usual way. Upon receipt of the medicinal product for external use, the production method is not limited, and the preparation can be carried out in the usual way. Thus, for the preparation of a medicament for external use, various types of raw materials that are commonly used for medicines, quasi-drugs, cosmetics or the like can be used as an ingredient in the base. Particular examples of the base ingredient that is used include animal and vegetable oils, mineral oils, essential oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyalcohols, water-soluble polymers, clay minerals, purified water etc. Then, a pH adjuster, an antioxidant, a chelating agent, an antibacterial and antifungal agent, a colorant, a flavoring agent and / or the like can be added, if necessary. The topical drug ingredient of the present invention is not limited to the aforementioned ingredients. If necessary, other ingredients may be added, and examples of this include an ingredient having a differentiation inducing activity, a blood circulation enhancer, a bactericide, an anti-inflammatory agent, a cell activator, a vitamin, an amino acid, a moisturizer, a keratolytic agent, etc. The amount of the base ingredient to be added is determined so that the concentration is the concentration of the base ingredient common in the preparation of a medicament for external use.

The compound of the present invention can be used in a therapeutic method for treating a disease in which tau, β-secretase or Aβ is involved. Particular examples of such a method include the following (a) to (c):

(a) a therapeutic method for treating a disease in which tau is involved, comprising the step of administering a compound represented by general formula (I), or a salt thereof, to a patient with a disease in which tau is involved;

(b) a therapeutic method for treating a disease in which β-secretase is involved, comprising the step of administering a compound represented by general formula (I), or a salt thereof, to a patient with a disease in which β-secretase is involved; and

(c) a therapeutic method for treating a disease in which Aβ is involved, comprising the step of administering a compound represented by general formula (I), or a salt thereof, to a patient with a disease in which Aβ is involved.

The compound of the present invention can also be used in a method for inhibiting tau aggregation, a method for inhibiting β-secretase, and a method for inhibiting Aβ aggregation. Particular examples of such a method include the following (d) to (i):

(d) a method of inhibiting tau aggregation, comprising the step of administering a compound represented by general formula (I) or a salt thereof to a human, thereby inhibiting tau aggregation in the human body;

(e) a method of inhibiting tau aggregation, comprising the step of bringing the compound represented by general formula (I) or a salt thereof into contact with tau;

(f) a method for inhibiting β-secretase, comprising the step of administering a compound represented by general formula (I) or a salt thereof to a human, thereby inhibiting β-secretase in the human body;

(g) a method for inhibiting β-secretase, comprising the step of bringing the compound represented by general formula (I) or a salt thereof into contact with β-secretase;

(h) a method for inhibiting Aβ aggregation, comprising the step of administering a compound represented by general formula (I) or a salt thereof to a human, thereby inhibiting Aβ aggregation in the human body; and

(i) a method of inhibiting Aβ aggregation, comprising the step of bringing the compound represented by general formula (I) or a salt thereof into contact with Aβ.

The salt in the above methods may be a pharmacologically acceptable salt.

EXAMPLES

The present invention will be described in further detail with reference to Examples, etc., but the present invention is not limited thereto. Various modifications of the present invention can be made by a person skilled in the art without going beyond the scope of the technical idea of the present invention.

In the Examples, synthetic compounds representing the structure of general formula (I) in which R is a hydrogen atom are found as a mixture of two tautomers represented by general formulas (I) and (I ') as shown below, depending on measurement conditions for ¹ H NMR. The tautomers represented by the general formulas (I) and (I ') are one and the same substance. Therefore, the synthetic compounds in the Examples can be called based either on the general formula (I) or on the general formula (I ').

The compound represented by the following general formula (II) corresponds to the compound represented by the above general formula (C), and is a synthesis intermediate that is included in the present invention. The compound represented by general formula (II) can exist in tautomeric forms, including the ketone form and the enol form, and these tautomeric forms are the same substance. Therefore, such a synthetic intermediate can be called based on any of the general formula (II), general formula (II ’) and general formula (II’ ’). The melting temperature may differ from the values shown in the Examples, depending on the crystalline system and / or the degree of contamination with impurities.

Example 1: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-4- (2-tetrahydrofuranylmethoxy) benzaldehyde

24.5 g (161 mmol) of 4-hydroxy-2-methoxybenzaldehyde were dissolved in 160 ml of N-methylpyrrolidone. To this solution 63 g (0.19 mol) of cesium carbonate and 40 g (0.24 mol) of tetrahydrofurfuryl bromide were added at room temperature, and the mixture was stirred at 80 ° C for 22 hours. Water (800 ml) was added to the resulting reaction mixture under ice-cooling, and extraction was performed with diethyl ether (500 ml × 3 times). The combined organic layer was washed with water and then with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting crude product was purified on basic alumina (hexane / ethyl acetate = 50/50 to 0/100) to obtain 23.7 g (62% yield) of the target compound in the form of a light yellow powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (m, 4H), 3.74 (m, 1H), 3.84 (m, 1H), 3.97 (s, 3H ), 4.10 (m, 2H), 4.21 (m, 1H), 6.64 (ddd, J = 0.8, 2.2, 8.5 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 10.27 (d, J = 0.8 Hz, 1H). Melting point 73.3 ° C.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

19.3 mg (85.0 mmol) of 6- (1H-indol-6-yl) hex-5-ene-2,4-dione and 22 mg (0.32 mmol) of boron oxide were placed in a 20 ml reactor and they were dissolved in 0.4 ml of ethyl acetate. While stirring at 70 ° C, 20 mg (85 μmol) of 2-methoxy-4- (2-tetrahydrofuranylmethoxy) benzaldehyde and 32 μl (0.14 mmol) of triisopropyl borate were successively added. After the mixture was stirred at the same temperature for 1 hour, 18 μl (0.18 mmol) of piperidine was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (2 ml) of 1N was added to the reaction mixture at room temperature. hydrochloric acid and saturated saline, and the mixture was stirred for 5 minutes to 1 hour (then the mixture was neutralized with saturated aqueous sodium bicarbonate if necessary). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 10.2 mg (27% yield) of the target compound in the form of an orange powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (m, 4H), 3.74 (m, 1H), 3.84 (m, 1H), 3.95 (s, 3H ), 4.05 (m, 2H), 4.21 (m, 1H), 6.00 (s, 1H), 6.53 (br d, J = 3 Hz, 1H), 6.62 (dd , J = 2.2, 8.5 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 16 Hz, 1H), 6.82 (d , J = 16 Hz, 1H), 7.44 (dd, J = 1.7, 8.5 Hz, 1H), 7.47 (m, 1H), 7.63 (d, J = 8.3 Hz , 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.74 (br s, 1H), 7.78 (d, J = 16 Hz, 1H), 7.93 (d , J = 16 Hz, 1H), 10.5 (br s, NH). Melting point 159-161 ° C, MS (ESI +) m / z 446.3 (M + 1).

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] ethenyl] -1H-pyrazole

400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta- were dissolved in 4.5 ml of acetic acid 1,6-diene-3,5-dione. To this solution was added 0.45 g (9.0 mmol) of hydrazine monohydrate at room temperature, and the mixture was stirred at 60 ° C for 3 hours. The resulting reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol). The resulting solid was washed with an organic solvent to obtain 298 mg (75% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (m, 4H), 3.74 (m, 1H), 3.84 (m, 1H), 3.92 (s, 3H ), 4.01 (d, J = 5.0 Hz, 1H), 4.21 (m, 1H), 6.47 (brd, J = 3 Hz, 1H), 6.58 (dd, J = 2.2, 8.5 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.70 (s, 1H), 7.06 (d, J = 17 Hz, 1H ), 7.10 (d, J = 17 Hz, 1H), 7.32 (d, J = 17 Hz, 1H), 7.34 (dd, J = 1.7, 8.5 Hz, 1H), 7.35 (m, 1H), 7.39 (d, J = 17 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.59 (br s, 1H), 10.3 (br s, NH). Melting point 218-220 ° C, MS (ESI +) m / z 442.2 (M + 1).

Example 2: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-4- (2-pyridylmethoxy) benzaldehyde

8.00 g (52.6 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 14.5 g (105 mmol) of potassium carbonate and 9.06 g (55.2 mmol) of 2- were dissolved in 53 ml of N, N-dimethylformamide. chloromethylpyridine hydrochloride, and the solution was stirred at 50 ° C for 4 hours. 260 ml of water was added to the reaction mixture at room temperature, and the precipitated crystal was separated by filtration. The crystal was washed with water and dried under reduced pressure to obtain 11.5 g (82% yield) of the target compound in the form of a light gray-brown powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.97 (s, 3H), 5.31 (s, 2H), 6.74 (ddd, J = 0.8, 2.2, 8.5 Hz , 1H), 6.84 (d, J = 2.2 Hz, 1H), 7.34 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.73 (d , J = 8.5 Hz, 1H), 7.84 (dt, J = 1.9, 7.7 Hz, 1H), 8.60 (wide d, J = 5 Hz, 1H), 10.28 (d, J = 0.8 Hz, 1H). Melting point 93.6 ° C.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 1 (2), except that 21 mg (85 μmol) of 2-methoxy-4- (2-pyridylmethoxy) benzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy- 4- (2-tetrahydrofuranylmethoxy) benzaldehyde to obtain 12.4 mg (32% yield) of the target compound in the form of an orange powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.95 (s, 3H), 5.27 (s, 2H), 6.00 (s, 1H), 6.53 (brd, J = 3 Hz, 1H), 6.71 (dd, J = 2.2, 8.5 Hz, 1H), 6.78 (d, J = 16 Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.82 (d, J = 16 Hz, 1H), 7.33 (m, 1H), 7.44 (dd, J = 1.7, 8.5 Hz, 1H), 7, 47 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.74 (br s, 1H), 7.78 (d, J = 16 Hz, 1H), 7.84 (dt, J = 1.7, 7.7 Hz, 1H), 7.93 (d, J = 16 Hz, 1H), 8.60 (brd, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 165-168 ° C, MS (ESI +) m / z 453.2 (M + 1).

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 400 mg (0.884 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7 - [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 239 mg (60% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.92 (s, 3H), 5.24 (s, 2H), 6.47 (brd, J = 3 Hz, 1H), 6.67 ( dd, J = 2.2, 8.5 Hz, 1H), 6.70 (s, 1H), 6.75 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.32 (d, J = 17 Hz, 1H), 7.30-7.38 (m, 3H), 7.39 ( d, J = 17 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.55-7.59 (m, 2H), 7.59 (br s, 1H), 7.84 (dt, J = 1.7, 7.7 Hz, 1H), 8.60 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 237-239 ° C, MS (ESI +) m / z 449.2 (M + 1).

Example 3: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-hydroxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-hydroxy-4- (2-pyridylmethoxy) benzaldehyde

16.4 g (100 mmol) of 2-chloromethylpyridine hydrochloride were dissolved in 50 ml of water. To this solution was added 50 ml of chloroform. The solution was neutralized by adding a saturated aqueous solution of sodium bicarbonate at room temperature. The organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and 250 ml of acetonitrile was added to the residue to obtain a solution of 2-chloromethylpyridine in acetonitrile.

Separately, 13.8 g (100 mmol) of 2,4-dihydroxybenzaldehyde was dissolved in 250 ml of acetonitrile and 32.5 g (100 mmol) of cesium carbonate was added at room temperature. To this solution, a solution of 2-chloromethylpyridine in acetonitrile prepared in advance was added dropwise at 50 ° C. over 4 hours, and the mixture was stirred for 11 hours. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20 to 50/50) to obtain 6.10 g (27% yield) of the target compound in the form of a white solid.

¹ H NMR (δ, chloroform-d): 5.25 (s, 2H), 6.53 (d, J = 2.5 Hz, 1H), 6.65 (dd, J = 2.6, 8, 1 Hz, 1H), 7.25 (m, 1H), 7.45 (m, 2H), 7.73 (dt, J = 1.9, 7.7 Hz, 1H), 8.61 (d, J = 4.8 Hz, 1H), 9.73 (s, 1H), 11.4 (s, 1H). Melting point 89.2-89.7 ° C, MS (EI) m / z 229 (M ⁺ ).

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-hydroxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out using the same materials in the same relative amounts as in Example 1 (2), except that 908 mg (3.96 mmol) of 3-hydroxy-4- (2-pyridylmethoxy) benzaldehyde was used instead mg (85 μmol) of 2-methoxy-4- (2-tetrahydrofuranylmethoxy) benzaldehyde to obtain 356 mg (21% yield) of the target compound in the form of an orange powder with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 5.19 (s, 2H), 6.08 (s, 1H), 6.48 (m, 1H), 6.55-6.59 (m, 2H ), 6.79 (d, J = 16 Hz, 1H), 6.86 (d, J = 16 Hz, 1H), 7.35-7.37 (m, 1H), 7.41-7.43 (m, 1H), 7.47-7.50 (m, 2H), 7.58-7.60 (m, 2H), 7.70 (s, 1H), 7.74 (d, J = 16 Hz, 1H), 7.81 (d, J = 16 Hz, 1H), 3.14 (dt, J = 2.0, 7.7 Hz, 1H), 8.59 (m, 1H), 10, 4 (s, 1H), 11.4 (s, 1H), 16.4 (br s, 1H). Melting point 187.6-189.5 ° C.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-hydroxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 1 (3), except that 700 mg (1.61 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-hydroxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indole -yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 226 mg (32% yield) of the desired compound in the form of a light yellowish and white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.17 (s, 2H), 6.46 (m, 1H), 6.58-6.60 (m, 1H), 6.60 (s, 1H ), 6.68 (s, 1H), 7.09 (d, J = 16 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.29-7.34 (m, 3H ), 7.30 (d, J = 17 Hz, 1H), 7.40 (d, J = 16 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.52 ( d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.58 (s, 1 H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (m, 1H), 10.2 (br s, 1H). Melting point 202.5-203.5 ° C, MS (EI) m / z 434 (M ⁺ ), EI-HRMS m / z calculated for C ₂₇ H ₂₂ N ₄ O ₂ (M ⁺ ) 434.1743, found 434.1740.

Example 4: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 4- (2-pyridylmethoxy) benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde were dissolved in 5.0 ml of N, N-dimethylformamide. To this solution was added 3.26 g (10.0 mol) of cesium carbonate and 0.98 g (6.0 mmol) of 2-chloromethylpyridine hydrochloride at room temperature, and the mixture was stirred at 50 ° C overnight. The resulting reaction mixture was diluted with ethyl acetate (100 ml), washed with water and then with brine (30 ml each time), and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20 to 50/50) to obtain 821 mg (77% yield) of the target compound in the form of a light green crystal.

(2) Synthesis of 6- (1H-indol-5-yl) hex-5-en-2,4-dione

15.5 ml of ethyl acetate, 15.9 ml (155 mmol) of 2,4-pentanedione and 3.24 g (46.5 mmol) of boron oxide were placed in a 300 ml pear-shaped flask equipped with a cooling tube. 4.50 g (31.0 mmol) of 1H-indole-5-carboxaldehyde and a solution of 7.2 ml (31 mmol) of triisopropyl borate in ethyl acetate (31 ml) were added dropwise to the mixture with stirring at 70 ° C. The mixture was stirred at 70 ° C. for 30 minutes and a solution of 3.68 ml (37.2 mmol) of n-butylamine in ethyl acetate (9.3 ml) was added dropwise. With stirring at 85 ° C for 1 hour, the mixture was cooled to 50 ° C and 3N was added. hydrochloric acid (22 ml). The mixture was stirred at the same temperature for 10 minutes and neutralized with saturated sodium bicarbonate solution. The resulting solution was diluted with ethyl acetate, washed twice with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90/10 to 70/30) and crystallized (ethyl acetate / hexane) to obtain 3.46 g (49% yield) of the target compound in the form of a yellow powder with the following properties .

¹ H NMR (δ, acetone-d ₆ ): 2.11 (s, 3H), 5.81 (s, 1H), 6.53 (d, J = 3.1 Hz, 1H), 6.63 ( d, J = 16 Hz, 1H), 7.38 (m, 1H), 7.47 (m, 2H), 7.73 (d, J = 16 Hz, 1H), 7.87 (s, 1H) 10.49 (br s, NH). Melting point 136-137 ° C.

(3) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-peredylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

In a 20 ml reactor, 31.0 mg (136 μmol) of 6- (1H-indol-5-yl) hex-5-en-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide were placed, and dissolved in 0.88 ml of ethyl acetate. While stirring at 70 ° C., 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde and 62 μl (0.27 mmol) of triisopropyl borate were successively added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μl (27 μmol) of piperidine in ethyl acetate (0.135 ml) was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (0.4 ml) of 1N was added to the reaction mixture at room temperature. hydrochloric acid and saturated saline, and the mixture was stirred for 5 minutes to 1 hour (then the mixture was neutralized with saturated aqueous sodium bicarbonate if necessary). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 37.1 mg (65% yield) of the target compound in the form of a yellow powder.

(4) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6- was dissolved in 0.34 ml of acetic acid diene-3,5-dione. To this solution, 34 μl (0.70 mmol) of hydrazine monohydrate was added at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extraction was performed with ethyl acetate. The resulting organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol). The resulting solid was washed with an organic solvent to obtain 3.5 mg (24% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.22 (s, 2H), 6.48 (d, J = 3.1 Hz, 1H), 6.70 (s, 1H), 7.03 ( d, J = 17 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 17 Hz, 1H), 7.16 (d, J = 17 Hz , 1H), 7.30 (d, J = 17 Hz, 1H), 7.26-7.35 (m, 2H), 7.41 (dd, J = 1.5, 8.7 Hz, 1H) 7.43 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.55 (broad d, J = 7.7 Hz, 1H) 7.72 (br s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (broad d, J = 5 Hz, 1H), 10, 3 (br s, NH). Melting point 95-102 ° C, MS (ESI +) m / z 419.4 (M + 1).

Example 5: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 3-methoxy-4- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out in the same manner as in Example 4 (1), except that 761 mg (5.00 mmol) of 4-hydroxy-3-methoxybenzaldehyde was used instead of 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde to give 1.016 g (84% yield) of the target compound in the form of a light green crystal.

(2) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [3-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 4 (3), except that 33 mg (0.14 mmol) of 3-methoxy-4- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 42.3 mg (69% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [3-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 5.0 mg (34% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.93 (s, 3H), 5.20 (s, 2H), 6.48 (d, J = 3.2 Hz, 1H), 6.70 ( s, 1H), 6.99-7.09 (m, 4H), 7.15 (d, J = 17 Hz, 1H), 7.25-7.36 (m, 4H), 7.40 (dd , J = 1.4, 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.60 (wide d, J = 7.7 Hz, 1H), 7 71 (br s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.57 (bd, J = 5 Hz, 1H), 10.3 ( bs, NH). Melting point 96-101 ° C, MS (ESI +) m / z 449.4 (M + 1).

Example 6: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [4-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 4-methoxy-3- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out in the same manner as in Example 4 (1), except that 761 mg (5.00 mmol) of 3-hydroxy-4-methoxybenzaldehyde was used instead of 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde to give 989 mg (81% yield) of the target compound in the form of a light green crystal.

(2) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [4-methoxy-3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 4 (3), except that 33 mg (0.14 mmol) of 4-methoxy-3- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 38.9 mg (63% yield) of the target compound in the form of a yellow powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [4-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indole-5 -) - 7- [4-methoxy- 3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 3.8 mg (26% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.87 (s, 3H), 5.26 (s, 2H), 6.49 (d, J = 2.9 Hz, 1H), 6.75 ( s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 17 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7 11 (dd, J = 2.0, 8 Hz, 1H), 7.13 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.27-7 36 (m, 3H), 7.41 (dd, J = 1.4, 8.3 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.64 (br. d, J = 7.9 Hz, 1H), 7.71 (br s, 1H), 7.83 (dt, J = 1.8, 7.7 Hz, 1H), 8.59 (br d , J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 109-118 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 7: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 3- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out in the same manner as in Example 4 (1), except that 611 mg (5.00 mmol) of 3-hydroxybenzaldehyde was used instead of 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde to give 772 mg (72 % yield) of the target compound in the form of a white powder.

(2) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [3- (2-) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 4 (3), except that 29 mg (0.14 mmol) of 3- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2 -pyridylmethoxy) benzaldehyde to obtain 24.9 mg (43% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [3- ( 2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4 - (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 9.4 mg (63% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.25 (s, 2H), 6.49 (d, J = 2.9 Hz, 1H), 6.75 (s, 1H), 6.95 ( ddd, J = 1, 2.5, 8.1 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.17 (brd, J = 8 Hz, 1H), 7, 18 (m, 2H), 7.25-7.36 (m, 5H), 7.41 (dd, J = 1.5, 8.5 Hz, 1H), 7.43 (d, J = 8, 5 Hz, 1H), 7.58 (brd, J = 7.9 Hz, 1H), 7.72 (br s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.59 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 183-186 ° C, MS (ESI +) m / z 419.3 (M + 1).

Example 8: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out in the same manner as in Example 4 (1), except that 611 mg (5.00 mmol) of 2-hydroxybenzaldehyde was used instead of 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde to give 882 mg (83 % yield) of the target compound in the form of a light brown powder.

(2) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [2- (2-dilmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 4 (3), except that 29 mg (0.14 mmol) of 2- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2 -pyridylmethoxy) benzaldehyde to obtain 36.3 mg (63% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [2- ( 2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4 - (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 9.9 mg (67% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 5.30 (s, 2H), 6.44 (br s, 1H), 6.69 (s, 1H), 6.9-7.4 (m , 10H), 7.49 (d, J = 17 Hz, 1H), 7.58 (broad d, J = 7.9 Hz, 1H), 7.64 (wide d, J = 8 Hz, 1H ), 7.66 (br s, 1H), 7.88 (br, J = 7.7 Hz, 1H), 8.60 (br, J = 5 Hz, 1H), 11.2 (bs, NH). Melting point 220-223 ° C, MS (ESI +) m / z 419.3 (M + 1).

Example 9: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-5- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out in the same manner as in Example 4 (1), except that 761 mg (5.00 mmol) of 5-hydroxy-2-methoxybenzaldehyde was used instead of 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde to give 1.018 g (84% yield) of the target compound in the form of a white amorphous solid.

(2) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy-5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 4 (3), except that 33 mg (0.14 mmol) of 2-methoxy-5- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to obtain 30.6 mg (50% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy -5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 9.2 mg (62% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.85 (s, 3H), 5.20 (s, 2H), 6.49 (d, J = 3.1 Hz, 1H), 6.73 ( s, 1H), 6.94 (dd, J = 2.6, 9.0 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.19 (d, J = 17 Hz, 1H), 7.33 (d, J = 17 Hz, 1H), 7.26-7.36 (m, 3H), 7.41 ( dd, J = 1.5, 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 17 Hz, 1H), 7.58 ( br d, J = 7.7 Hz, 1H), 7.73 (br s, 1H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 116-122 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 10: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 6- (1H-indol-3-yl) hex-5-en-2,4-dione

The synthesis was carried out in the same manner as in Example 4 (2), except that 4.50 g (31.0 mmol) of 1H-indole-3-carboxaldehyde was used instead of 4.50 g (31.0 mmol) of 1H -indole-5-carboxaldehyde, obtaining 2.14 g (30% yield) of the target compound in the form of a yellow powder.

¹ H NMR (δ, acetone-d ₆ ): 2.08 (s, 3H), 5.81 (s, 1H), 6.66 (d, J = 16 Hz, 1H), 7.1-7, 3 (m, 2H), 7.51 (m, 1H), 7.85 (s, 1H), 7.89 (d, J = 16 Hz, 1H), 8.00 (m, 1H). Melting point 155-158 ° C.

(2) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

In a 20 ml reactor, 31.0 mg (136 μmol) of 6- (1H-indol-3-yl) hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide were placed, and dissolved in 0.88 ml of ethyl acetate. While stirring at 70 ° C., 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde and 62 μl (0.27 mmol) of triisopropyl borate were successively added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μl (27 μmol) of piperidine in ethyl acetate (0.135 ml) was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (0.4 ml) of 1N was added to the reaction mixture at room temperature. hydrochloric acid and saturated saline, and the mixture was stirred for 5 minutes to 1 hour (then the mixture was neutralized if necessary with saturated aqueous sodium bicarbonate). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 25.7 mg (45% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-3-yl) -7- [4- ( 2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4 - (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 5.8 mg (39% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.21 (s, 2H), 6.46 (dd, J = 1, 3.0 Hz, 1H), 6.69 (s, 1H), 7, 02 (d, J = 17 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.1-7.2 (m, 2H), 7.32 (m, 1H), 7.43 (d, J = 17 Hz, 1H), 7.46 (m, 1H) 7.52 (d, J = 8.8 Hz, 2H), 7.53-7.60 (m, 2H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.96 (m, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 196-199 ° C, MS (ESI +) m / z 419.3 (M + 1).

Example 11: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [3-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 10 (2), except that 33 mg (0.14 mmol) of 3-methoxy-4- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 29.2 mg (47% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-3-yl) -7- [3-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 8.4 mg (57% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.93 (s, 3H), 5.20 (s, 2H), 6.69 (s, 1H), 7.0-7.13 (m, 5H ), 7.1-7.2 (m, 2H), 7.27 (d, J = 2 Hz, 1H), 7.30 (m, 1H), 7.43 (d, J = 17 Hz, 1H ), 7.47 (m, 1H), 7.60 (s, 1H), 7.61 (d, J = 7 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz , 1H), 7.96 (m, 1H), 8.56 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 120-130 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 12: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [4-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [4-methoxy-3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 10 (2), except that 33 mg (0.14 mmol) of 4-methoxy-3- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 26.3 mg (43% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [4-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-3-yl) -7- [4-methoxy -3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 5.9 mg (40% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.80 (s, 3H), 5.23 (s, 2H), 6.64 (s, 1H), 6.94 (d, J = 17 Hz, 1H), 6.9-7.2 (m, 6H), 7.30 (br s, 1H), 7.32 (d, J = 17 Hz, 1H), 7.35 (m, 1H), 7.42 (br d, J = 7.4 Hz, 1H), 7.56 (br d, J = 7.6 Hz, 1H), 7.63 (br s, 1H), 7.88 (br.t, J = 7.7 Hz, 1H), 7.87 (br.d, J = 8 Hz, 1H), 8.59 (br.j, J = 5 Hz, 1H), 11.4 (bs, NH). Melting point 232-243 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 13: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 10 (2), except that 29 mg (0.14 mmol) of 3- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2 -pyridylmethoxy) benzaldehyde to obtain 15.7 mg (27% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-3-yl) - [3- (2- pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2 -pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 5.7 mg (38% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.25 (s, 2H), 6.73 (s, 1H), 6.94 (ddd, J = 1, 2.6, 8.2 Hz, 1H ), 7.10 (d, J = 17 Hz, 1H), 7.11-7.21 (m, 5H), 7.25-7.30 (m, 2H), 7.33 (m, 1H) 7.44 (d, J = 17 Hz, 1H), 7.46 (m, 1H), 7.56-7.62 (m, 2H), 7.82 (dt, J = 1.8, 7 , 7 Hz, 1H), 7.96 (m, 1H), 8.59 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 198-201 ° C, MS (ESI +) m / z 419.4 (M + 1).

Example 14: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [2- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 10 (2), except that 29 mg (0.14 mmol) of 2- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2 -pyridylmethoxy) benzaldehyde to obtain 34.6 mg (60% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indole-3 -) - 7- [2- (2 -pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- ( 2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 7.8 mg (53% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.31 (s, 2H), 6.71 (s, 1H), 6.99 (dd, J = 7.7 Hz, 1H), 7.08 ( d, J = 7.5 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.1-7.2 (m, 2H), 7.23 (d, J = 17 Hz, 1H), 7.25 (m, 1H), 7.32 (m, 1H), 7.44 (d, J = 17 Hz, 1H), 7.46 (m, 1H), 7.57-7, 65 (m, 3H), 7.67 (dd, J = 1.4, 7.8 Hz, 1H), 7.85 (dt, J = 1.8, 7.7 Hz, 1H), 7.97 (m, 1H), 8.60 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 114-125 ° C, MS (ESI +) m / z 419.4 (M + 1).

Example 15: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy-5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 10 (2), except that 33 mg (0.14 mmol) of 2-methoxy-5- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 38.0 mg (62% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy -5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 7.3 mg (49% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.85 (s, 3H), 5.20 (s, 2H), 6.71 (s, 1H), 6.93 (dd, J = 2.6 , 8.9 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.1-7.2 (m, 2H ), 7.19 (d, J = 17 Hz, 1H), 7.31 (m, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 17 Hz, 1H), 7.46 (d, J = 17 Hz, 1H), 7.46 (m, 1H), 7.56-7.62 (m, 2H), 7.82 (dt, J = 1 8, 7.7 Hz, 1H), 7.97 (m, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 233-238 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 16: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

In a 20 ml reactor, 31.0 mg (136 μmol) of 6- (1H-indol-6-yl) hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide were placed, and dissolved in 0.88 ml of ethyl acetate. While stirring at 70 ° C., 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde and 62 μl (0.27 mmol) of triisopropyl borate were successively added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μl (27 μmol) of piperidine in ethyl acetate (0.135 ml) was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (0.4 ml) of 1N was added to the reaction mixture. hydrochloric acid and saturated saline at room temperature, and the mixture was stirred for 5 minutes to 1 hour (then the mixture was neutralized if necessary with saturated aqueous sodium bicarbonate). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 41.3 mg (72% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [4- ( 2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4 - (2-pyridylmethoxy) phenyl] -hepta-1,6-diene-3,5-dione, obtaining 5.2 mg (35% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.21 (s, 2H), 6.46 (dd, J = 1, 3.0 Hz, 1H), 6.71 (s, 1H), 7, 03 (d, J = 17 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 17 Hz, 1H), 7.16 (d, J = 17 Hz, 1H), 7.26-7.36 (m, 4H), 7.52 (d, J = 8.8 Hz, 2H), 7.53-7.6 (m, 3H), 7, 82 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 211-214 ° C, MS (ESI +) m / z 419.3 (M + 1).

Example 17: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [3-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 3-methoxy-4- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to obtain 29.7 mg (48% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [3-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 9.3 mg (63% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.17 (s, 2H), 6.41 (br s, 1H), 6.70 (s, 1H), 6.94-7.1 (m, 5H), 7.17-7.30 (m, 3H), 7.31-7.38 (m, 2H), 7.47-7.55 (m, 3H) ), 7.84 (br d, J = 8 Hz, 1H), 8.57 (br d, J = 4 Hz, 1H), 11.2 (br s, NH). Melting point 236-243 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 18: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [4-methoxy-3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 4-methoxy-3- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 32.0 mg (52% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [4-methoxy -3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy)] hepta-1,6-diene-3,5-dione, obtaining 9.9 mg (67% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.87 (s, 3H), 5.26 (s, 2H), 6.46 (dd, J = 0.8, 3.2 Hz, 1H), 6.70 (s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.11 (m, 1H), 7.13 (d, J = 17 Hz, 1H), 7.25-7.38 (m, 5H), 7.53-7.58 (m, 2H ), 7.64 (d, J = 7.9 Hz, 1H), 7.83 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz , 1H), 10.3 (br s, NH). Melting point 110-117 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 19: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 29 mg (0.14 mmol) of 3- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2 -pyridylmethoxy) benzaldehyde to obtain 23.4 mg (41% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-6-yl) - [3- (2- pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) - [4- (2-pyridylmethoxy ) phenyl] hepta-1,6-diene-3,5-dione, obtaining 10.7 mg (72% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.25 (s, 2H), 6.46 (dd, J = 0.8, 3.2 Hz, 1H), 6.76 (s, 1H), 6.95 (ddd, J = 1, 2.6, 8.1 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.17 (brd, J = 8 Hz, 1H ), 7.18 (m, 2H), 7.23-7.38 (m, 6H), 7.53-7.62 (m, 3H), 7.82 (dt, J = 1.8, 7 , 7 Hz, 1H), 8.59 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 193-195 ° C, MS (ESI +) m / z 419.4 (M + 1).

Example 20: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 29 mg (0.14 mmol) of 2- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2 -pyridylmethoxy) benzaldehyde to give 37.0 mg (64% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-6-yl) - [2- (2- pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2 -pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 9.7 mg (65% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.31 (s, 2H), 6.46 (dd, J = 0.9, 3.1 Hz, 1H), 6.74 (s, 1H), 6.99 (dd, J = 7.4, 7.4 Hz, 1H), 7.08 (dd, J = 0.9, 8.2 Hz, 1H), 7.10 (d, J = 17 Hz , 1H), 7.22 (m, 1H), 7.23 (d, J = 17 Hz, 1H), 7.28-7.36 (m, 4H), 7.54-7.59 (m, 2H), 7.62 (d, J = 17 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.67 (dd, J = 1.7, 7.8 Hz, 1H), 7.85 (dt, J = 1.8, 7.7 Hz, 1H), 8.60 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 113-120 ° C, MS (ESI +) m / z 419.3 (M + 1).

Example 21: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 2-methoxy-5- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 42.1 mg (68% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy -5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy)] hepta-1,6-diene-3,5-dione, obtaining 11.6 mg (78% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.85 (s, 3H), 5.19 (s, 2H), 6.46 (dd, J = 0.8, 3.1 Hz, 1H), 6.73 (s, 1H), 6.94 (dd, J = 2.6, 9.0 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 7.10 (d , J = 17 Hz, 1H), 7.19 (d, J = 17 Hz, 1H), 7.27-7.38 (m, 5H), 7.45 (d, J = 17 Hz, 1H), 7.53-7.62 (m, 3H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 10 , 3 (br s, NH). Melting point 111-120 ° C, MS (ESI +) m / z 449.4 (M + 1).

Example 22: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-3- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (1), except that 100 mg (0.657 mmol) of 3-hydroxy-2-methoxybenzaldehyde was used instead of 611 mg (5.00 mmol) 4-hydroxybenzaldehyde, yielding 66.8 mg (42% yield) of the target compound in the form of a white powder.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 2-methoxy-3- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 40.6 mg (66% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-3- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy -3- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 8.4 mg (57% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.25 (s, 2H), 6.46 (dd, J = 0.8, 3.2 Hz, 1H), 6.78 (s, 1H), 7.0-7.06 (m, 2H), 7.11 (d, J = 17 Hz, 1H), 7.19 (d, J = 17 Hz, 1H), 7.27-7.38 (m, 5H), 7.50 (d, J = 17 Hz, 1H), 7.54-7.60 (m, 2H), 7.64 (d, J = 7, 9 Hz, 1H), 7.84 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 109-114 ° C, MS (ESI +) m / z 449.3 (M + 1).

Example 23: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] - [(1E) -2- [4-methoxy-2- (2-pyridylmethoxy) phenyl] ethenyl] -1H pyrazole

(1) Synthesis of 4-methoxy-2- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (1), except that 100 mg (0.657 mmol) of 2-hydroxy-4-methoxybenzaldehyde was used instead of 611 mg (5.00 mmol) 4-hydroxybenzaldehyde to give 69.3 mg (43% yield) of the target compound in the form of a white powder.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [4-methoxy-2- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 4-methoxy-2- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 42.7 mg (69% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4-methoxy-2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [4-methoxy -2- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 7.5 mg (50% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.79 (s, 3H), 5.30 (s, 2H), 6.46 (brd, J = 3 Hz, 1H), 6.59 ( dd, J = 2, 8.6 Hz, 1H), 6.67 (d, J = 2 Hz, 1H), 6.68 (s, 1H), 7.09 (d, J = 17 Hz, 1H) 7.10 (d, J = 17 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.29-7.36 (m, 3H), 7.52 (d, J = 17 Hz, 1H), 7.53-7.58 (m, 2H), 7.57 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H) 7.85 (br t, J = 7.7 Hz, 1H), 8.60 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 107-115 ° C, MS (ESI +) m / z 449.4 (M + 1).

Example 24: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [5-methoxy-2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 5-methoxy-2- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (1), except that 100 mg (0.657 mmol) of 2-hydroxy-5-methoxybenzaldehyde was used instead of 611 mg (5.00 mmol) 4-hydroxybenzaldehyde, yielding 77.3 mg (48% yield) of the target compound in the form of a white powder.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [5-methoxy-2- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 5-methoxy-2- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 29.4 mg (48% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [5-methoxy-2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [5-methoxy -2- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 7.0 mg (47% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.75 (s, 3H), 5.22 (s, 2H), 6.41 (br s, 1H), 6.71 (s, 1H), 6.81 (brd, J = 9 Hz, 1H), 7.01 (d, J = 9 Hz, 1H), 7.01 (d, J = 17 Hz, 1H), 7.18 (d, J = 17 Hz, 1H), 7.17-7.6 (m, 9H), 7.87 (dd, J = 1.6, 7.7 Hz, 1H), 8.59 (wide d, J = 5 Hz, 1H), 11.2 (br s, NH). Melting point 119-124 ° C, MS (ESI +) m / z 449.4 (M + 1).

Example 25: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 3-methoxy-5- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (1), except that 100 mg (0.657 mmol) of 3-hydroxy-5-methoxybenzaldehyde was used instead of 611 mg (5.00 mmol) 4-hydroxybenzaldehyde, affording 85.6 mg (54% yield) of the target compound in the form of a white powder.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [3-methoxy-5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 3-methoxy-5- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to obtain 22.8 mg (37% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [3-methoxy-5- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [3-methoxy -5- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 8.5 mg (57% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.82 (s, 3H), 5.23 (s, 2H), 6.46 (brd, J = 3 Hz, 1H), 6.54 ( dd, J = 2.2, 2.2 Hz, 1H), 6.75 (s, 1H), 6.76 (br s, 1H), 6.86 (br s, 1H), 7.10 (d, J = 17 Hz, 1H), 7.13 (d, J = 17 Hz, 1H), 7.18 (d, J = 17 Hz, 1H), 7.27-7.38 (m, 4H ), 7.51-7.60 (m, 3H), 7.85 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (wide d, J = 5 Hz, 1H) 10.3 (br s, NH). Melting point 88-93 ° C, MS (ESI +) m / z 449.4 (M + 1).

Example 26: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-piperidinoethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-4- (2-piperidinoethoxy) benzaldehyde

304 mg (2.00 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 0.55 g (4.0 mmol) of potassium carbonate and 64 mg (0.20 mmol) of tetrabutylammonium bromide were dissolved in 2.0 ml of N, N-dimethylformamide. . 0.74 g (4.0 mmol) of 1- (2-chloroethyl) piperidine hydrochloride was added to this solution, and the mixture was stirred at 100 ° C. overnight. The resulting reaction mixture was diluted with ethyl acetate (100 ml), washed with water and then with brine (each time in an amount of 20 ml), and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 90/10) to obtain 88.9 mg (16% yield) of the target compound in the form of a brown viscous substance.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy- (2-piperidinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 36 mg (0.14 mmol) of 2-methoxy-4- (2-piperidinoethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to obtain 46.3 mg (75% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-piperidinoethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (32 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy -4- (2-piperidinoethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 7.7 mg (52% yield) of the target compound in the form of a light yellowish-white powder with the following properties .

¹ H NMR (δ, acetone-d ₆ ): 1.41 (m, 2H), 1.54 (m, 4H), 2.47 (m, 4H), 2.69 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 4.12 (t, J = 6.0 Hz, 2H), 6.46 (dd, J = 0.8, 3.1 Hz, 1H), 6.56 (d, J = 2.4, 8.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.68 (s, 1H), 7.04 (d , J = 17 Hz, 1H), 7.08 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.3-7.38 (m, 2H), 7.38 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.54-7.60 (m, 2H), 10.3 (br s , NH). Melting point 150-155 ° C, MS (ESI +) m / z 469.4 (M + 1).

Example 27: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-morpholinoethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-4- (2-morpholinoethoxy) benzaldehyde

The synthesis was carried out in the same manner as in Example 26 (1), except that 0.74 g (4.0 mmol) of 4- (2-chloroethyl) morpholine hydrochloride was used instead of 0.74 g (4.0 mmol) ) 1- (2-chloroethyl) piperidine hydrochloride to give 302 mg (56% yield) of the target compound in the form of a brown viscous substance.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 36 mg (0.14 mmol) of 2-methoxy-4- (2-morpholinoethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 50.1 mg (82% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-morpholinoethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (32 μmol) (1E, 6E) -1- (1H-indol-6-yl) - [2-methoxy-4 - (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [ 4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-

dione, receiving 9.2 mg (62% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.52 (t, J = 4.6 Hz, 4H), 2.74 (t, J = 5.8 Hz, 2H), 3.61 (t, J = 4.6 Hz, 4H), 3.90 (s, 3H), 4.16 (t, J = 5.8 Hz, 2H), 6.46 (dd, J = 1, 3.1 Hz, 1H), 6.57 (dd, J = 2.4, 8.4 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.68 (s, 1H), 7, 04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.30-7.36 (m, 2H), 7.37 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.53-7.60 (m, 2H), 10.3 ( bs, NH). Melting point 113-122 ° C, MS (ESI +) m / z 471.4 (M + 1).

Example 28: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- [2- (4-methylpiperazino) ethoxy ] phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-4- [2- (4-methylpiperazino) ethoxy] benzaldehyde

To a solution of 304 mg (2.00 mmol) of 4-hydroxy-2-methoxybenzaldehyde in N, N-dimethylformamide (4.0 ml) was added 105 mg (55%, 2.40 mmol) of sodium hydride at room temperature. The mixture was stirred at room temperature for 30 minutes and 0.69 ml (8.0 mmol) of ethylene dibromide was added. The mixture was stirred at 80 ° C for 7 hours and 2.2 ml (20 mmol) of 1-methylpiperazine was added. The mixture was stirred at 80 ° C. overnight. Water was added to the reaction mixture under ice cooling, and extraction was performed with ethyl acetate. The resulting organic layer was washed with saturated sodium bicarbonate solution and then with saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 40/60) to obtain 115 mg (20% yield) of the target compound in the form of a brown viscous substance.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- [2- (4-methylpiperazino) ethoxy] phenyl] hepta-1,6-diene -3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 38 mg (0.14 mmol) of 2-methoxy-4- [2- (4-methylpiperazino) ethoxy] benzaldehyde was used instead of 29 mg ( 0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde to give 40.9 mg (65% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- [2- (4-methylpiperazino) ethoxy ] phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (31 μmol) (1E, 6E) -1- (1H-indol-yl) -7- [2-methoxy-4 - [2- (4-methylpiperazino) ethoxy] phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole-5- yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 8.8 mg (59% yield) of the desired compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.18 (s, 3H), 2.37 (br s, 4H), 2.55 (br s, 4H), 2.74 (t, J = 5.9 Hz, 2H), 3.90 (s, 3H), 4.13 (t, J = 5.9 Hz, 2H), 6.46 (wide d, J = 3.1 Hz, 1H ), 6.56 (dd, J = 2.3, 8.4 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.68 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.31 (d, J = 17 Hz, 1H), 7.30-7.36 (m, 2H ), 7.37 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.53-7.59 (m, 2H), 10.3 (broad .s, NH). Melting point 134-142 ° C, MS (ESI +) m / z 484.4 (M + 1).

Example 29: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4 - [(β-D-glucopyranosyl) oxy] -2- methoxyphenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 2-methoxy-4 - [(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) oxy] benzaldehyde

An aqueous solution of 1N. sodium hydroxide (10.4 ml) was added to a solution of 666 mg (4.38 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 1.50 g (3.65 mmol) of 2,3,4,6-tetra-O-acetyl α-D-glucopyranosyl bromide and 1.18 g (3.66 mmol) of tetrabutylammonium bromide in chloroform (11 ml) at room temperature, and the mixture was vigorously stirred for 1 hour. The reaction mixture was subjected to extraction with ethyl acetate. After washing with saturated sodium bicarbonate solution and then with saturated saline, drying over magnesium sulfate was carried out. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 75/25 to 60/40) to obtain 606 mg (40% yield) of 2-methoxy-4 - [(2,3,4,6-tetra- O-acetyl-β-D-glucopyranosyl)] benzaldehyde in the form of a white powder.

(2) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4 - [(2,3,4,6-tetra-O-acetyl-β-D -glucopyranosyl) oxy] phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 65 mg (0.14 mmol) of 2-methoxy-4 - [(2,3,4,6-O-acetyl-β- D-glucopyranosyl) oxy] benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde to obtain 83.0 mg (92% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4 - [(β-D-glucopyranosyl) oxy] -2- methoxyphenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (22 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy -4 - [(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) oxy] phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione to give 14.7 mg crude product, 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4 - [(2,3,4,6-O-acetyl- β-D-glucopyranosyl) oxy] -2-methoxyphenyl] ethenyl] -1H-pyrazole.

14.7 mg of the above compound was dissolved in 1.0 ml of tetrahydrofuran, and a solution of 5.4 mg (0.10 mmol) of sodium methylate in methanol (1.0 ml) was added at room temperature. The mixture was stirred at the same temperature for 1 hour and neutralized with 100 μl of 1N. hydrochloric acid (0.10 mmol). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 95/5 to 70/30) to obtain 5.9 mg (53% yield in 2 steps) of the target compound in the form of a light yellowish-white powder with the following properties .

¹ H NMR (δ, DMSO-d ₆ ): 3.84 (s, 3H), 4.64 (m, 1H), 4.90 (m, 1H), 5.07 (m, 1H), 5, 14 (m, 1H), 5.34 (m, 1H), 6.41 (br s, 1H), 6.65 (brd, J = 9 Hz, 1H), 6.69 (s, 1H ), 6.72 (d, J = 2.4 Hz, 1H), 6.99 (wide d, J = 17 Hz, 2H), 7.20-7.40 (m, 4H), 7.47 7.60 (m, 3H); 11.2 (br s, NH). Melting point 194-199 ° C, MS (ESI +) m / z 520.3 (M + 1).

Example 30: Synthesis of 3 - [(1E) -2- (1H-benzotriazol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of 6- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hex-5-en-2,4-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (2), except that 10.0 g (41.1 mmol) of 2-methoxy-4- (2-pyridylmethoxy) benzaldehyde instead of 4.50 g (31.0 mmol) of 1H-indole-5-carboxaldehyde, obtaining 5.65 g (42% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.10 (s, 3H), 3.92 (s, 3H), 5.25 (s, 2H), 5.75 (s, 1H), 6, 63 (d, J = 16 Hz, 1H), 6.67 (dd, J = 2.4, 8.6 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 7, 32 (m, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.82 (dt, J = 1.8 , 7.8 Hz, 1H), 7.85 (d, J = 16 Hz, 1H), 8.58 (m, 1H). Melting point 81-82 ° C, MS (ESI +) m / z 326.2 (M + 1).

(2) Synthesis of (1E, 6E) -1- (1H-benzotriazol-5-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

44.3 mg (136 μmol) of 6- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hex-5-en-2,4-dione and 13.2 mg (0.190 mmol) were placed in a 20 ml reactor boron oxide, and they were dissolved in 0.88 ml of ethyl acetate. While stirring at 70 ° C., 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde and 62 μl (0.27 mmol) of triisopropyl borate were successively added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μl (27 mmol) of piperidine in ethyl acetate (0.135 ml) was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (0.4 ml) of 1N was added to the reaction mixture at room temperature. hydrochloric acid and saturated saline, and the mixture was stirred for 5 minutes to 1 hour (then the mixture was neutralized if necessary with saturated aqueous sodium bicarbonate). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 5.9 mg (10% yield) of the target compound in the form of an orange powder.

(3) Synthesis of 3 - [(1E) -2- (1H-benzotriazol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-benzotriazol-5-yl) -7- [2-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] -hepta-1,6-diene-3,5-dione, obtaining 1.7 mg (11% yield) of the target compound in the form of a light yellowish-white powder with the following properties .

Melting point 113-120 ° C, MS (ESI +) m / z 451.2 (M + 1).

Example 31: Synthesis of 3 - [(1E) -2- (1H-benzimidazol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-benzimidazol-5-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 30 (2), except that 20 mg (0.14 mmol) of 1H-benzimidazole-5-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5 β-carboxaldehyde, obtaining 15.1 mg (24% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-benzimidazol-5-yl) ethenyl] -5 - [(1E) -2- [2- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (33 μmol) (1E, 6E) -1- (1H-benzimidazol-5-yl) -7- [2-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 4.8 mg (32% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3, 8.6 Hz, 1H), 6.71 (s, 1H), 6.74 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.13 (d, J = 17 Hz, 1H), 7.28-7.4 (m, 2H), 7.39 (d, J = 17 Hz, 1H), 7.45-7.75 (m, 5H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.15 (s, 1H), 8.58 (brd, J = 5 Hz, 1H), 11.6 (br s, NH). Melting point 135-142 ° C, MS (ESI +) m / z 450.3 (M + 1).

Example 32: Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (quinoxaline-6-yl) ethenyl] -1H pyrazole

(1) Synthesis of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (quinoxaline-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 30 (2), except that 21 mg (0.14 mmol) of quinoxaline-6-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde yielding 19.4 mg (31% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (quinoxaline-6-yl) ethenyl] -1H pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (32 μmol) (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7 - (quinoxalin-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [ 4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 4.0 mg (27% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.8 Hz, 1H), 6.74 ( d, J = 2 Hz, 1H), 6.79 (s, 1H), 6.99 (d, J = 17 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.30 -7.46 (m, 3H), 7.50 (m, 1H), 7.54 (d, J = 8 Hz, 1H), 7.85 (d, J = 1.8, 7.7 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 8.12 (br s, 1H), 8.18 (br s, 1H), 8.59 (br d, J = 5 Hz, 1H), 8.88 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 1.7 Hz, 1H). Melting point 205-213 ° C, MS (ESI +) m / z 462.2 (M + 1).

Example 33: Synthesis of 3 - [(1E) -2- (benzofuran-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H pyrazole

(1) Synthesis of (1E, 6E) -1- (benzofuran-2-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 186 μl (1.54 mmol) of benzofuran-2-carboxaldehyde was used instead of 20 mg (0.14 mmol) 1H-benzotriazole-5-carboxaldehyde, obtaining 169 mg (24% yield) of the target compound in the form of a red powder with the following properties.

¹ H NMR (δ, chloroform-d): 3.88 (s, 3H), 5.25 (s, 2H), 5.86 (s, 1H), 6.59-6.61 (m, 2H) 6.65 (d, J = 16 Hz, 1H), 6.77 (d, J = 15 Hz, 1H), 6.91 (s, 1H), 7.21-7.25 (m, 2H) , 7.34 (m, 1H), 7.46-7.51 (m, 4H), 7.57 (d, J = 7.2 Hz, 1H), 7.73 (dt, J = 1.6 , 7.7 Hz, 1H), 7.93 (d, J = 16 Hz, 1H), 8.61 (m, 1H), 15.9 (br s, 1H). Melting point 125.8-127.7 ° C, MS (EI) m / z 453 (M ⁺ ), EI-HRMS m / z calculated for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 453.1576, found 453 , 1576.

(2) Synthesis of 3 - [(1E) -2- (benzofuran-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 100 mg (0.221 mmol) (1E, 6E) -1- (benzofuran-2-yl) -7 - [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole-5 -yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 21.0 mg (21% yield) of the target compound in the form of a light brown powder with the following properties.

¹ H NMR (δ, chloroform-d): 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.62 (m, 3H), 6.69 (s, 1H) 6.95 (d, J = 17 Hz, 1H), 7.00 (d, J = 16 Hz, 1H), 7.17-7.30 (m, 3H), 7.24 (d, J = 16 Hz, 1H), 7.31 (d, J = 17 Hz, 1H), 7.42-7.47 (m, 2H), 7.52 (d, J = 11 Hz, 2H), 7.72 (dt, J = 1.9, 7.7 Hz, 1H), 8.61 (m, 1H). Melting point 199.4-200.9 ° C, MS (EI) m / z 449 (M ⁺ ), EI-HRMS m / z calculated for C ₂₈ H ₂₃ N ₃ O ₃ (M ⁺ ) 449.1739, found 449.1743.

Example 34: Synthesis of 3 - [(1E) -2- (benzothiophen-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H pyrazole

(1) Synthesis of (1E, 6E) -1- (benzothiophen-2-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 150 μl (0.923 mmol) of benzothiophene-2-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H- benzotriazole-5-carboxaldehyde, obtaining 97 mg (22% yield) of the target compound in the form of a yellow powder with the following properties.

¹ H NMR (δ, chloroform-d): 3.88 (s, 3H), 5.25 (s, 2H), 5.82 (s, 1H), 6.46 (d, J = 15 Hz, 1H ), 6.61-6.58 (m, 2H), 6.64 (d, J = 16 Hz, 1H), 6.91 (s, 1H), 7.23-7.25 (m, 2H) 7.34-7.36 (m, 1H), 7.44 (s, 1H), 7.47-7.52 (m, 2H), 7.71-7.80 (m, 3H), 7 82 (d, J = 15 Hz, 1H), 7.92 (d, J = 16 Hz, 1H), 8.61 (m, 1H), 15.9 (m, 1H). Melting point 187.7-188.4 ° C, MS (EI) m / z 469 (M ⁺ ), EI-HRMS m / z calculated for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 469.1348, found 469 , 1351.

(2) Synthesis of 3 - [(1E) -2- (benzothiophen-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 40 mg (0.085 mmol) (1E, 6E) -1- (benzothiophen-2-yl) -7 - [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole-5 -yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 8.0 mg (20% yield) of the target compound in the form of a light yellowish white powder with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.22 (s, 2H), 6.63-6.77 (m, 3H), 6.86-7.01 (m, 2H), 7.23-7.37 (m, 4H), 7.42-7.56 (m, 4H), 7.77-7.93 (m, 2H), 7.85 (dt , J = 1.9, 7.7 Hz, 1H), 8.59 (m, 1H), 13.0 (m, 1H). Melting point 231.1-232.1 ° C, MS (EI) m / z 465 (M ⁺ ), EI-HRMS m / z calculated for C ₂₈ H ₂₃ N ₃ O ₂ S (M ⁺ ) 465.1511, found 465.1509.

Example 35: Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (1-methyl-1H-indole-6- il) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (1-methyl-1H-indol-6-yl) hepta-1,6-diene- 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 391 mg (2.46 mmol) of 1-methyl-1H-indole-6-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde, to obtain 367 mg (32% yield) of the target compound in the form of an orange powder with the following properties.

¹ H NMR (δ, chloroform-d): 3.83 (s, 3H), 3.88 (s, 3H), 5.25 (s, 2H), 5.83 (s, 1H), 6.48 (d, J = 3.1 Hz, 1H), 6.59-6.60 (m, 2H), 6.63 (d, J = 16 Hz, 1H), 6.66 (d, J = 16 Hz , 1H), 7.12 (d, J = 3.1 Hz, 1H), 7.23-7.25 (m, 1H), 7.37 (dd, J = 1.0, 8.2 Hz, 1H), 7.47-7.52 (m, 3H), 7.60 (d, J = 8.2 Hz, 1H), 7.73 (dt, J = 2.1, 7.7 Hz, 1H ), 7.81 (d, J = 16 Hz, 1H), 7.90 (d, J = 16 Hz, 1H), 8.61 (m, 1H), 16.1 (br s, 1H). Melting point 190.6-191.6 ° C, MS (EI) m / z 466 (M ⁺ ), EI-HRMS m / z calculated for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 466.1893, found 466 , 1891.

(2) Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (1-methyl-1H-indole-6- il) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 130 mg (0.279 mmol) (1E, 6E) -1- [2-methoxy-4- (2 -pyridylmethoxy) phenyl] -7- (1-methyl-1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 48 mg (37% yield) of the target compound in the form yellow powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.86 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 6.42 (m, 1H), 6, 66 (dd, J = 2.6, 8.4 Hz, 1H), 6.69 (s, 1H), 6.75 (d, J = 2.6 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.23 (d, J = 2.9 Hz, 1H), 7.30-7.37 (m, 3H), 7.39 (d, J = 17 Hz, 1H), 7.52-7.58 (m, 4 H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8, 58 (m, 1H), 11.9 (br s, 1H). Melting point 172.0-174.0 ° C, MS (EI) m / z 462 (M ⁺ ), EI-HRMS m / z calculated for C ₂₉ H ₂₆ N ₄ O ₂ (M ⁺ ) 462.2056, found 462,2060.

Example 36: Synthesis of 3 - [(1E) -2- (1H-indol-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-2-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 220 mg (1.54 mmol) of 1H-indole-2-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde, to obtain 64 mg (9.2% yield) of the target compound in the form of an orange powder with the following properties.

¹ H NMR (δ, chloroform-d): 3.87 (s, 3H), 5.25 (s, 2H), 5.79 (s, 1H), 6.40 (d, J = 15 Hz, 1H ), 6.57-6.61 (m, 2H), 6.62 (d, J = 16 Hz, 1H), 6.83 (m, 1H), 7.12 (d, J = 7.6 Hz , 1H), 7.23-7.27 (m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.47-7.52 (m, 2H), 7.60- 7.65 (m, 2H), 7.92 (d, J = 16 Hz, 1H), 8.29 (br s, 1H), 8.61 (m, 1H), 15.8 (s, 1H ) Melting point 177.7-179.4 ° C, MS (EI) m / z 452 (M ⁺ ), EI-HRMS m / z calculated for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 452.1736, found 452 , 1737.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 100 mg (0.221 mmol) (1E, 6E) -1- (1H-indol-2-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole -5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 49 mg (49% yield) of the target compound in the form of a light yellowish white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.23 (s, 2H), 6.59 (m, 1H), 6.66 (dd, J = 2.6 , 8.7 Hz, 1H), 6.69 (s, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.99 (m, 1H), 7.06 (d, J = 17 Hz, 1H), 7.10 (m, 1H), 7.11 (d, J = 17 Hz, 1H) 7.24 (d, J = 16 Hz, 1H), 7.30-7.37 (m, 2H), 7.39 (d, J = 16 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H ), 7.57 (d, J = 7.7 Hz, 1H), 7.82 (dt, J = 2.0, 7.7 Hz, 1H), 8.59 (m, 1H), 10.5 (broad s, 1H); 12.1 (broad s, 1H). Melting point 150.8-151.6 ° C, MS (EI) m / z 448 (M ⁺ ), EI-HRMS m / z calculated for C ₂₈ H ₂₄ N ₄ O ₂ (M ⁺ ) 448.1899, found 448,1897.

Example 37: Synthesis of 3 - [(1E) -2- (2-benzyloxy-4-diethylaminophenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (2-benzyloxy-4-diethylaminophenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 16 (1), except that 411 mg (1.45 mmol) of 2-benzyloxy-4-diethylaminobenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, to obtain 482 mg (74% yield) of the target compound in the form of a black powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.14 (t, J = 7.2 Hz, 3H), 3.45 (q, J = 7.2 Hz, 4H), 5.28 (s , 2H), 5.85 (s, 1H), 6.35-6.40 (m, 2H), 6.51 (m, 1H), 6.65 (d, J = 16 Hz, 1H), 6 74 (d, J = 16 Hz, 1H), 7.34-7.46 (m, 5H), 7.41 (d, J = 8.7 Hz, 1H), 7.54-7.56 ( m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.72 (d, J = 15 Hz, 1H), 8.01 (d, J = 16 Hz, 1H), 10.4 (br s, 1H), 16.7 (br s, 1H). Melting point 160.1-162.9 ° C, MS (EI) m / z 492 (M ⁺ ).

(2) Synthesis of 3 - [(1E) -2- (2-benzyloxy-4-diethylaminophenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 300 mg (0.609 mmol) (1E, 6E) -1- (2-benzyloxy-4-diethylaminophenyl) -7- (1H-indole -6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- ( 2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 11.4 mg (3.83% yield) of the target compound in the form of a light brown powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.11 (t, J = 7.2, 3H), 3.39 (q, J = 7.2, 4H), 5.25 (s, 2H ), 6.33-6.53 (m, 2H), 6.46 (m, 1H), 6.60 (s, 1H), 6.97 (d, J = 17 Hz, 1H), 7.10 (d, J = 16 Hz, 1H), 7.28 (d, J = 16 Hz, 1H), 7.39-7.45 (m, 3H), 7.46 (d, J = 17 Hz, 1H ), 7.54-7.58 (m, 4H), 10.3 (s, 1H), 11.9 (br s, 1H). Melting point 78.1-80.0 ° C, MS (EI) m / z 488 (M ⁺ ), EI-HRMS m / z calculated for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 488.2576, found 488 , 2574.

Example 38: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 40 mg (0.27 mmol) of 1H-indole-3-carboxaldehyde was used instead of 20 mg (0.14 mmol) 1H-benzotriazole-5-carboxaldehyde, to obtain 81.2 mg (67% yield) of the target compound in the form of a black powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 4.8 mg (32% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.64 (dd, J = 2.4, 8.4 Hz, 1H), 6.65 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.11-7.19 (m, 2H), 7.31 (dd, J = 5.1, 7.2 Hz, 1H), 7.37 (d, J = 17 Hz, 1H), 7.43 (d, J = 17 Hz, 1H), 7.45 (dd, J = 1.4, 6.8 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.97 (broad d, J = 7.2 Hz, 1H), 8.58 (brd, J = 4 Hz, 1H), 10.5 (br s, NH). Melting point 112-116 ° C, MS (ESI +) m / z 449.2 (M + 1).

Example 39: Synthesis of 3 - [(1E) -2- (1H-indol-4-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-4-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 40 mg (0.27 mmol) of 1H-indole-4-carboxaldehyde was used instead of 20 mg (0.14 mmol) 1H-benzotriazole-5-carboxaldehyde, obtaining 32.9 mg (27% yield) of the target compound in the form of a black powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-4-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-4-yl) -7- [2-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 5.8 mg (39% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.78 (s, 1H), 6.88 (d, J = 3 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.29-7.44 (m, 5H), 7.53 ( d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 17 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 10.4 (br.s, NH). Melting point 108-113 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 40: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 40 mg (0.27 mmol) of 1H-indole-5-carboxaldehyde was used instead of 20 mg (0.14 mmol) 1H-benzotriazole-5-carboxaldehyde, to obtain 108 mg (89% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 4.6 mg (31% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.48 (d, J = 3.0 Hz, 1H), 6.65 ( dd, J = 2.4, 8.6 Hz, 1H), 6.67 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 17 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.28-7.34 (m, 3H), 7.37 (d, J = 17 Hz, 1H), 7.41 ( m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.81 ( dt, J = 1.7, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 98-104 ° C, MS (ESI +) m / z 449.2 (M + 1).

Example 41: Synthesis of 3 - [(1E) -2- (1H-indol-7-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-7-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 30 (2), except that 20 mg (0.14 mmol) of 1H-indole-7-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5 -carboxaldehyde, obtaining 17.3 mg (28% yield) of the target compound in the form of a black powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-7-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-7-yl) -7- [2-methoxy -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 6.1 mg (41% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.51 (d, J = 3.1 Hz, 1H), 6.65 ( dd, J = 2.4, 8.6 Hz, 1H), 6.74 (s, 1H), 6.74 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 7 , 8 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.23 (d, J = 17 Hz, 1H), 7.31 (dd, J = 5.7 Hz, 1H) , 7.38 (d, J = 17 Hz, 1H), 7.38 (broad d, J = 3.1 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7 , 52 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 17 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (wide d, J = 5 Hz, 1H), 10.6 (bs, NH). Melting point 99-110 ° C, MS (ESI +) m / z 449.0 (M + 1).

Example 42: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy-4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 10 (2), except that 33 mg (0.14 mmol) of 2-methoxy-4- (3-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to obtain 20.7 mg (34% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy -4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 2.7 mg (18% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.66 (s, 1H), 6.68 (dd, J = 2.3 , 8.6 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.1-7.2 (m, 2H), 7.37 (d, J = 17 Hz, 1H), 7.40 (m, 1H), 7.42 (d, J = 17 Hz, 1H), 7.45 (dd, J = 1.7, 5.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H) 7.59 (s, 1H), 7.89 (broad d, J = 7.8 Hz, 1H), 7.97 (wide d, J = 6.8 Hz, 1H), 8.55 (dd, J = 2.5, 4.8 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 10.5 (br s, NH). Melting point 129-137 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 43: Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy-4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 10 (2), except that 33 mg (0.14 mmol) of 2-methoxy-4- (4-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde, to obtain 61 mg (quantitative yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-3-yl) -7- [2-methoxy -4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 3.4 mg (23% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.24 (s, 2H), 6.64 (dd, J = 2.3, 8.5 Hz, 1H), 6.65 (s, 1H), 6.73 (d, J = 2.3 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.1-7.2 (m, 2H), 7.37 (d, J = 17 Hz, 1H), 7.43 (d, J = 17 Hz, 1H), 7.43-7, 46 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.97 (brd, J = 7.2 Hz, 1H), 8.59 (dd, J = 1.4, 4.4 Hz, 2H); 10.5 (br s, NH). Melting point 128-139 ° C, MS (ESI +) m / z 449.2 (M + 1).

Example 44: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy-4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 4 (3), except that 33 mg (0.14 mmol) of 2-methoxy-4- (3-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde, to obtain 32.4 mg (53% yield) of the target compound in the form of a brown powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy -4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 2.8 mg (19% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.48 (d, J = 3.0 Hz, 1H), 6.67 ( dd, J = 2.4, 8.5 Hz, 1H), 6.68 (s, 1H), 6.71 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.28-7.34 (m, 3H), 7.38 (d, J = 17 Hz, 1H), 7.38- 7.42 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.89 (brd, J = 7.9 Hz, 1H ), 8.55 (dd, J = 1.4, 4.7 Hz, 1H), 8.71 (br s, 1H), 10.3 (br s, NH). Melting point 127-135 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 45: Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy-4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 4 (3), except that 33 mg (0.14 mmol) of 2-methoxy-4- (4-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde, to give 30.4 mg (50% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [2-methoxy -4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 2.9 mg (19% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.24 (s, 2H), 6.48 (d, J = 2.7 Hz, 1H), 6.65 ( dd, J = 2.4, 8.5 Hz, 1H), 6.67 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.28-7.36 (m, 3H), 7.38-7.46 (m, 4H), 7.53 (d , J = 8.5 Hz, 1H), 7.72 (s, 1H), 8.58 (brd, J = 4 Hz, 2H), 10.3 (br s, NH). Melting point 133-141 ° C, MS (ESI +) m / z 449.0 (M + 1).

Example 46: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 2-methoxy-4- (3-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde, to obtain 31.0 mg (51% yield) of the target compound in the form of a brown powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy -4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 5.0 mg (33% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.45 (dd, J = 0.7, 3.0 Hz, 1H), 6.67 (dd, J = 2.4, 8.4 Hz, 1H), 6.69 (s, 1H), 6.72 (d, J = 2.4 Hz, 1H), 7.06 (d , J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.3, 8 , 2 Hz, 1H), 7.34 (m, 1H), 7.38 (d, J = 17 Hz, 1H), 7.40 (dd, J = 4.8, 7.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.57 (br s, 1H), 7.89 (br. D , J = 7.8 Hz, 1H), 8.55 (dd, J = 1.5, 4.7 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 10.3 (bs, NH). Melting point 90-95 ° C, MS (ESI +) m / z 449.2 (M + 1).

Example 47: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 2-methoxy-4- (4-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 42.0 mg (69% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy -4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 5.0 mg (33% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.24 (s, 2H), 6.45 (brd, J = 3 Hz, 1H), 6.65 ( dd, J = 2.4, 8.6 Hz, 1H), 6.68 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8.2 Hz, 1H), 7.34 (m, 1H), 7.37 (d, J = 17 Hz, 1H), 7.45 (wide d, J = 5 Hz, 2H), 7.53 (d, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.57 (br s, 1H), 8.59 (dd, J = 1.4, 4.5 Hz, 2H) 10.3 (br s, NH). Melting point 103-118 ° C, MS (ESI +) m / z 449.2 (M + 1).

Example 48: Synthesis of 3 - [(1E) -2- (1H-indol-4-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-4-yl) -7- [2-methoxy-4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

In a 20 ml reactor, 31.0 mg (136 μmol) of 6- (1H-indol-4-yl) hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide were placed, and dissolved in 0.88 ml of ethyl acetate. While stirring at 70 ° C, 33 mg (0.14 mmol) of 2-methoxy-4- (3-pyridylmethoxy) benzaldehyde and 62 μl (0.27 mmol) of triisopropyl borate were successively added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μl (27 μmol) of piperidine in ethyl acetate (0.135 ml) was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (0.4 ml) of 1N was added to the reaction mixture at room temperature. hydrochloric acid and saturated saline, and the mixture was stirred for 5 minutes to 1 hour (then the mixture was neutralized if necessary with saturated aqueous sodium bicarbonate). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 42.8 mg (70% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-4-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-4-yl) -7- [2-methoxy -4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 6.4 mg (43% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.68 (dd, J = 2.4, 8.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.78 (s, 1H), 6.88 (broad d, J = 3 Hz, 1H), 7.08 (d, J = 17 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H) 7.36-7.42 (m, 4H), 7.55 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 17 Hz, 1H), 7.89 (br. d, J = 7.8 Hz, 1H), 8.56 (dd, J = 1.6, 4.7 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 10, 4 (bs, NH). Melting point 109-114 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 49: Synthesis of 3 - [(1E) -2- (1H-indol-4-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-4-yl) -7- [2-methoxy-4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 49 (1), except that 33 mg (0.14 mmol) of 2-methoxy-4- (4-pyridylmethoxy) benzaldehyde was used instead of 33 mg (0.14 mmol) 2-methoxy-4- (3-pyridylmethoxy) benzaldehyde, to obtain 56.0 mg (92% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-4-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-4-yl) -7- [2-methoxy -4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 9.1 mg (61% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.24 (s, 2H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.78 (s, 1H), 6.88 (d, J = 3 Hz, 1H), 7.08 (d, J = 17 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.32-7.42 (m, 4H), 7.46 ( broad d, J = 5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 17 Hz, 1H), 8.59 (wide d, J = 5 Hz, 2H), 10.4 (br s, NH). Melting point 207-215 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 50: Synthesis of 3 - [(1E) -2- (1H-indol-7-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-7-yl) -7- [2-methoxy-4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

88 mg (0.27 mmol) of 6- [2-methoxy-4- (3-pyridylmethoxy) phenyl] hex-5-en-2,4-dione and 26.4 mg (0.380 mmol) were placed in a 20 ml reactor boron oxide, and they were dissolved in 1.76 ml of ethyl acetate. While stirring at 70 ° C., 40 mg (0.27 mmol) of 1H-indole-7-carboxaldehyde and 124 μl (0.54 mmol) of triisopropyl borate were successively added to the mixture. After the mixture was stirred at the same temperature for 1 hour, a solution of 5.4 μl (54 μmol) of piperidine in ethyl acetate (0.27 ml) was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (0.8 ml) of 1N was added to the reaction mixture at room temperature. hydrochloric acid and saturated saline, and the mixture was stirred for 5 minutes to 1 hour (then, if necessary, the mixture was neutralized with saturated aqueous sodium bicarbonate). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 21.6 mg (18% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-7-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-7-yl) -7- [2-methoxy -4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 7.2 mg (48% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.52 (d, J = 3.2 Hz, 1H), 6.68 ( dd, J = 2.3, 8.5 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.74 (s, 1H), 7.06 (t, J = 7 , 7 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.23 (d, J = 17 Hz, 1H), 7.38 (d, J = 17 Hz, 1H), 7 40 (m, 1H), 7.38 (broad d, J = 3.4 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 17 Hz, 1H), 7.89 (brd, J = 7.8 Hz , 1H), 8.56 (br d, J = 5 Hz, 1H), 8.71 (br s, 1H), 10.6 (br s, NH). Melting point 122-129 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 51: Synthesis of 3 - [(1E) -2- (1H-indol-7-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-7-yl) -7- [2-methoxy-4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

88 mg (0.27 mmol) of 6- [2-methoxy-4- (4-pyridylmethoxy) phenyl] hex-5-en-2,4-dione and 26.4 mg (0.380 mmol) were placed in a 20 ml reactor boron oxide, and they were dissolved in 1.76 ml of ethyl acetate. While stirring at 70 ° C., 40 mg (0.27 mmol) of 1H-indole-7-carboxaldehyde and 124 μl (0.54 mmol) of triisopropyl borate were successively added to the mixture. After the mixture was stirred at the same temperature for 1 hour, a solution of 5.4 μl (54 μmol) of piperidine in ethyl acetate (0.27 ml) was added, and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1: 1 solution (0.8 ml) of 1N. hydrochloric acid and saturated saline at room temperature, and the mixture was stirred for 5 minutes to 1 hour (then, if necessary, the mixture was neutralized with saturated aqueous sodium bicarbonate). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 43.5 mg (36% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-7-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-7-yl) -7- [2-methoxy -4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 3.4 mg (23% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.25 (s, 2H), 6.52 (brd, J = 3.2 Hz, 1H), 6, 65 (dd, J = 2.4, 8.5 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.74 (s, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.23 (d, J = 17 Hz, 1H), 7.38 (d, J = 17 Hz, 1H) 7.38 (br d, J = 3.2 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.46 (br d, J = 5.8 Hz, 2H), 7.52 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 17 Hz, 1H), 8 59 (br d, J = 5 Hz, 2H); 10.7 (br s, NH). Melting point 201-206 ° C, MS (ESI +) m / z 449.2 (M + 1).

Example 52: Synthesis of 3 - [(1E) -2- (1H-indol-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-2-yl) -7- [2-methoxy-4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 51 (1), except that 40 mg (0.27 mmol) of 1H-indole-2-carboxaldehyde was used instead of 40 mg (0.27 mmol) of 1H-indole-7 -carboxaldehyde, obtaining 44.4 mg (36% yield) of the target compound in the form of a brown powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (3-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-2-yl) -7- [2-methoxy -4- (3-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 6.3 mg (42% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.58 (s, 1H), 6.68 (dd, J = 2.3 , 8.6 Hz, 1H), 6.69 (s, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.98 (t, J = 7 Hz, 1H), 7, 04-7.14 (m, 3H), 7.24 (d, J = 17 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 17 Hz, 1H), 7.40 (dd, J = 5.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.89 (brd, J = 7.8 Hz, 1H), 8.56 (dd, J = 1.4, 4.7 Hz, 1H), 8.71 (d, J = 1 Hz, 1H), 10.6 (br s, NH). Melting point 126-138 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 53: Synthesis of 3 - [(1E) -2- (1H-indol-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-2-yl) -7- [2-methoxy-4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5- dion

In a 20 ml reactor, 31.0 mg (136 μmol) of 6- (1H-indol-2-yl) hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide were placed, and dissolved in 0.88 ml of ethyl acetate. While stirring at 70 ° C, 33 mg (0.14 mmol) of 2-methoxy-4- (4-pyridylmethoxy) benzaldehyde and 62 μl (0.27 mmol) of triisopropyl borate were successively added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μl (27 μmol) of piperidine in ethyl acetate (0.135 ml) was added, and the mixture was further stirred for 1 hour. A 1: 1 solution (0.4 ml) of 1N was added to the reaction mixture at room temperature. hydrochloric acid and saturated saline, and the mixture was stirred for 5 minutes to 1 hour (then, if necessary, the mixture was neutralized with saturated aqueous sodium bicarbonate). The resulting organic phase was directly purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol) to obtain 47.3 mg (78% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-2-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-2-yl) -7- [2-methoxy -4- (4-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7 - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 2.8 mg (19% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.24 (s, 2H), 6.58 (s, 1H), 6.65 (dd, J = 2.4 , 8.5 Hz, 1H), 6.69 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.98 (br t, J = 7 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.09 (m, 1H), 7.10 (d, J = 17 Hz, 1H), 7.23 (d, J = 17 Hz, 1H) , 7.34 (d, J = 8 Hz, 1H), 7.38 (d, J = 17 Hz, 1H), 7.46 (broad d, J = 5 Hz, 2H), 7.48 (d , J = 8 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 8.58 (dd, J = 1.4, 4.4 Hz, 2H), 10.5 (broad .s, NH). Melting point 124-134 ° C, MS (ESI +) m / z 449.1 (M + 1).

Example 54: Synthesis of 3 - [(1E) -2- (2,4-dimethoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (2,4-dimethoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 21 mg (0.14 mmol) of 2,4-dimethoxybenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, obtaining 43.6 mg (87% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (2,4-dimethoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (40 μmol) (1E, 6E) -1- (2,4-dimethoxyphenyl) -7- (1H-indole-6 -yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2- pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 8.6 mg (57% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.82 (s, 3H), 3.89 (s, 3H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.56 ( dd, J = 2.3, 8.5 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.30-7.35 (m, 2H), 7.37 ( d, J = 17 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 121-133 ° C, MS (ESI +) m / z 372.2 (M + 1).

Example 55: Synthesis of 3 - [(1E) -2- [4- (acetylamino) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [4- (acetylamino) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 22 mg (0.14 mmol) of 4- (acetylamino) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy ) benzaldehyde, obtaining 40.6 mg (81% yield) of the target compound in the form of a red powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [4- (acetylamino) phenyl] ethenyl] -5 - [(1E) -2- (1H-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (40 μmol) (1E, 6E) -1- [4- (acetylamino) phenyl] -7- (1H-indole- 6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) - [4- (2-pyridylmethoxy ) phenyl] hepta-1,6-diene-3,5-dione, obtaining 5.4 mg (36% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.07 (s, 3H), 6.45 (dd, J = 1.3 Hz, 1H), 6.72 (s, 1H), 7.06 ( d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.29 (d, J = 17 Hz, 1H ), 7.31 (dd, J = 2, 8 Hz, 1H), 7.34 (d, J = 3 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7, 55 (d, J = 8 Hz, 1H), 7.57 (br s, 1H), 7.66 (d, J = 8.6 Hz, 2H), 10.3 (br s, NH). Melting point> 300 ° C, MS (ESI +) m / z 369.2 (M + 1).

Example 56: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-phenoxyphenyl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- (4-phenoxyphenyl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 27 mg (0.14 mmol) of 4-phenoxybenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, receiving 40.1 mg (73% yield) of the target compound in the form of a yellow powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-phenoxyphenyl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (37 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- (4-phenoxyphenyl ) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] -hepta-1,6-diene-3,5-dione, obtaining 6.9 mg (46% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 6.45 (brd, J = 3 Hz, 1H), 6.74 (s, 1H), 7.01 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8 Hz, 2H), 7.09 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.15 (t , J = 7.5 Hz, 1H), 7.20 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.2 , 8.2 Hz, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7.40 (t, J = 8 Hz, 2H), 7.55 (d, J = 8 Hz, 1H), 7.57 (br s, 1H), 7.58 (d, J = 9 Hz, 2H), 10.3 (br s, NH). Melting point 175-182 ° C, MS (ESI +) m / z 404.2 (M + 1).

Example 57: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4- (methanesulfonyl) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (methanesulfonyl) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 25 mg (0.14 mmol) of 4- (methanesulfonyl) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy ) benzaldehyde, obtaining 14.4 mg (28% yield) of the target compound in the form of a yellow powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [4- (methanesulfonyl) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 12 mg (31 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (methanesulfonyl) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) - 7- [4- (2-pyridylmethoxy)] hepta-1,6-diene-3,5-dione, obtaining 4.8 mg (40% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.12 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.82 (s, 1H), 7.11 ( d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.30-7.36 (m, 3H), 7.38 (d, J = 17 Hz, 1H) 7.56 (d, J = 8 Hz, 1H), 7.58 (br s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H); 10.3 (br s, NH). Melting point 260-268 ° C, MS (ESI +) m / z 390.2 (M + 1).

Example 58: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (5-methoxy-2-nitrophenyl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- (5-methoxy-2-nitrophenyl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 25 mg (0.14 mmol) of 5-methoxy-2-nitrobenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2- pyridylmethoxy) benzaldehyde, obtaining 24.0 mg (46% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (5-methoxy-nitrophenyl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 18 mg (47 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- (5-methoxy-2-nitrophenyl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 14.1 mg (78% yield) of the target compound in the form of a yellow powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 4.00 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.81 (s, 1H), 7.04 ( dd, J = 2.8, 9.1 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.21 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.4, 8 Hz, 1H), 7.33-7.38 (m, 3H), 7.56 (d, J = 8.2 Hz, 1H), 7.58 (br s, 1H ), 7.67 (d, J = 17 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 10.3 (br s, NH). Melting point 104-109 ° C, MS (ESI) m / z 387.0 (M + 1).

Example 59: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2- (3-pyridyl) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2- (3-pyridyl) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 25 mg (0.14 mmol) of 2- (3-pyridyl) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2 -pyridylmethoxy) benzaldehyde, to obtain 51.1 mg (96% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2- (3-pyridyl) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (52 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2- (3-pyridyl) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl ) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 10.8 mg (54% yield) of the desired compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 6.45 (dd, J = 0.8, 3.1 Hz, 1H), 6.56 (s, 1H), 7.06 (d, J = 17 Hz, 1H), 7.08 (d, J = 17 Hz, 1H), 7.14 (d, J = 17 Hz, 1H), 7.25 (d, J = 17 Hz, 1H), 7.29 (dd, J = 1.2, 8 Hz, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7.33-7.6 (m, 6H), 7.69 (m, 1H), 7.79 (ddd, J = 1.8, 2.2, 7.9 Hz, 1H), 7.85 (broad d, J = 7.7 Hz, 1H), 8.61 (d , J = 1.7 Hz, 1H), 10.3 (br s, NH). Melting point 248-255 ° C, MS (ESI +) m / z 389.0 (M + 1).

Example 60: Synthesis of 3 - [(1E) -2- (2-bromo-5-hydroxy-4-methoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] - 1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (2-bromo-5-hydroxy-4-methoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 31 mg (0.14 mmol) of 2-bromo-5-hydroxy-4-methoxybenzaldehyde was used instead of 29 mg (0.14 mmol) 4 - (2-pyridylmethoxy) benzaldehyde, obtaining 20.7 mg (35% yield) of the target compound in the form of a yellow powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (2-bromo-5-hydroxy-4-methoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] - 1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 15 mg (34 μmol) (1E, 6E) -1- (2-bromo-5-hydroxy-4-methoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 5.2 mg (35% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.75 (s, 1H), 6.94 ( s, 1H), 6.99 (d, J = 17 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.14 (s, 1H), 7.29 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.2, 8 Hz, 1H), 7.35 (m, 1H), 7.37 (d, J = 17 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.58 (br s, 1H), 10.3 (br s, NH). Melting point 137-142 ° C, MS (ESI +) m / z 435.9 (M + 1).

Example 61: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-phenylphenyl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- (4-phenylphenyl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 25 mg (0.14 mmol) of 4-phenylbenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, receiving 33.3 mg (64% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-phenylphenyl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (52 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- (4-phenylphenyl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [ 4- (2-pyridylmethoxy)] hepta-1,6-diene-3,5-dione, obtaining 3.9 mg (20% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 6.46 (dd, J = 1.3 Hz, 1H), 6.78 (s, 1H), 7.11 (d, J = 17 Hz, 1H) , 7.22 (d, J = 17 Hz, 1H), 7.26 (d, J = 17 Hz, 1H), 7.32 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.5, 8 Hz, 1H), 7.32-7.38 (m, 2H), 7.46 (dd, J = 7.4, 7.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.58 (br s, 1H), 7.65-7.7 (m, 6H), 10.3 (br s, NH). Melting point 273-276 ° C, MS (ESI +) m / z 388.1 (M + 1).

Example 62: Synthesis of 3 - [(1E) -2- [2-bromo-4- (4-methylpiperazin-1-yl) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6- il) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [2-bromo-4- (4-methylpiperazin-1-yl) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene 3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 38 mg (0.14 mmol) of 2-bromo-4- (4-methylpiperazin-1-yl) benzaldehyde was used instead of 29 mg (0 , 14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, to obtain 56.4 mg (86% yield) of the target compound in the form of a brown powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [2-bromo-4- (4-methylpiperazin-1-yl) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6- il) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (41 μmol) (1E, 6E) -1- [2-bromo-4- (4) -methylpiperazin-1-yl) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione to give 8.1 mg (41% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.25 (s, 3H), 2.48 (t, J = 5.0 Hz, 2H), 3.24 (t, J = 5.0 Hz, 2H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.73 (s, 1H), 6.97 (d, J = 17 Hz, 1H), 7.01 (dd, J = 2.3, 8.8 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.4, 8.4 Hz, 1H), 7.34 (m, 1H), 7.39 (d, J = 17 Hz, 1H), 7 55 (d, J = 8.3 Hz, 1H), 7.58 (br s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 10.3 (br s, NH). Melting point 120-124 ° C, MS (ESI +) m / z 488.1 (M + 1).

Example 63: Synthesis of 3 - [(1E) -2- (4-benzyloxy-2-methoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (4-benzyloxy-2-methoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 33 mg (0.14 mmol) of 4-benzyloxy-2-methoxybenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2- pyridylmethoxy) benzaldehyde, obtaining 59.2 mg (98% yield) of the target compound in the form of a black powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (4-benzyloxy-2-methoxyphenyl)] - 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (45 mmol) (1E, 6E) -1- (4-benzyloxy-2-methoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 10.2 mg (51% yield) of the desired compound in the form of a yellowish-white powder with the following properties .

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 5.15 (s, 2H), 6.45 (dd, J = 1.3 Hz, 1H), 6.64 ( dd, J = 2.4, 8.5 Hz, 1H), 6.68 (s, 1H), 6.69 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 Hz, 1H) 7.32-7.36 (m, 3H), 7.40 (d, J = 7.2, 7.5 Hz, 2H), 7.49 (d, J = 7.0 Hz, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s , NH). Melting point 86-91 ° C, MS (ESI +) m / z 448.1 (M + 1).

Example 64: Synthesis of 3 - [(1E) -2- [4- (diphenylmethoxy) -2-methoxyphenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H- pyrazole

(1) Synthesis of (1E, 6E) -1- [4- (diphenylmethoxy) -2-methoxyphenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 43 mg (0.14 mmol) of 4- (diphenylmethoxy) -2-methoxybenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- ( 2-pyridylmethoxy) benzaldehyde to obtain 59.9 mg (85% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [4- (diphenylmethoxy) -2-methoxyphenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H- pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (38 μmol) (1E, 6E) -1- [4- (diphenylmethoxy) -2- methoxyphenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole-5- il) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 12.5 mg (63% yield) of the desired compound in the form of a yellowish-white powder with following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.83 (s, 3H), 6.45 (brd, J = 3 Hz, 1H), 6.52 (s, H), 6.61 ( dd, J = 2.3, 8.6 Hz, 1H), 6.65 (s, 1H), 6.73 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 17 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.24-7.38 (m, 10H), 7.43 (d, J = 8.6 Hz, 1H), 7, 53-7.57 (m, 5H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 114-119 ° C, MS (ESI +) m / z 524.2 (M + 1).

Example 65: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-isopropoxy-2-methoxyphenyl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- (4-isopropoxy-2-methoxyphenyl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 26 mg (0.14 mmol) of 4-isopropoxy-2-methoxybenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2- pyridylmethoxy) benzaldehyde, obtaining 44.7 mg (83% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-isopropoxy-methoxyphenyl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (50 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- (4-isopropoxy-2-methoxyphenyl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-) phenyl] hepta-1,6-diene-3,5-dione, obtaining 11.1 mg (56% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.30 (d, J = 6.0 Hz, 6H), 3.88 (s, 3H), 4.66 (t, J, 6.0 = 6 , 0 Hz, 1H), 6.45 (dd, J = 1.3 Hz, 1H), 6.52-6.56 (m, 2H), 6.67 (s, 1H), 7.03 (d , J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 , 2 Hz, 1H), 7.34 (m, 1H), 7.37 (d, J = 17 Hz, 1H), 7.49 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 107-113 ° C, MS (ESI +) m / z 400.2 (M + 1).

Example 66: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-methoxyethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-methoxyethoxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 28 mg (0.14 mmol) of 2-methoxy-4- (2-methoxyethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to give 50.2 mg (90% yield) of the target compound in the form of a brown powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-methoxyethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (48 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole- 5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 11.8 mg (59% yield) of the desired compound in the form of a yellowish white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.36 (s, 3H), 3.70 (t, J = 4.7 Hz, 2H), 3.89 (s, 3H), 4.15 ( t, J = 4.7 Hz, 2H), 6.45 (dd, J = 1.3 Hz, 1H), 6.56 (d, J = 2.3, 8.5 Hz, 1H), 6, 59 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H) , 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8.2 Hz, 1H), 7.34 (m, 1H), 7.37 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H) 10.3 (br s, NH). Melting point 90-96 ° C, MS (ESI +) m / z 416.1 (M + 1).

Example 67: Synthesis of 3 - [(1E) -2- (2-bromo-5-methoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (2-bromo-5-methoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 29 mg (0.14 mmol) of 2-bromo-5-methoxybenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2- pyridylmethoxy) benzaldehyde, obtaining 35.2 mg (62% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (2-bromo-5-methoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (48 μmol) (1E, 6E) -1- (2-bromo-5-methoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 9.0 mg (45% yield) of the target compound in the form of a yellowish-white powder with the following properties .

¹ H NMR (δ, acetone-d ₆ ): 3.87 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.80 (s, 1H), 6.82 ( dd, J = 3.0, 8.8 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.19 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.4, 8 Hz, 1H), 7.34 (d, J = 17 Hz, 1H), 7.33-7.37 (m, 2H), 7.44 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.58 (br s, 1H), 10.3 ( bs, NH). Melting point 103-109 ° C, MS (ESI +) m / z 420.0 (M + 1).

Example 68: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-methoxybenzyloxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (4-methoxybenzyloxy) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 16 (1), except that 37 mg (0.14 mmol) of 2-methoxy-4- (4-methoxybenzyloxy) benzaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde to obtain 20.1 mg (31% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (4-methoxybenzyloxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 18 mg (38 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (4-methoxybenzyloxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole -5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 4.2 mg (23% yield) of the target compound in the form of a white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.80 (s, 3H), 3.89 (s, 3H), 5.06 (s, 2H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.63 (dd, J = 2.3, 8.4 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 6.68 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.3, 8 Hz, 1H), 7.34 (m, 1H), 7.37 (d, J = 17 Hz, 1H), 7 41 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.57 (broad s, 1H); 10.3 (broad s, NH). Melting point 211-214 ° C, MS (ESI +) m / z 478.1 (M + 1).

Example 69: Synthesis of 3 - [(1E) -2- (quinolin-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H pyrazole

(1) Synthesis of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (quinolin-5-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 40 mg (0.27 mmol) of quinoline-5-carboxaldehyde was used instead of 20 mg (0.14 mmol) 1H-benzotriazole-5-carboxaldehyde to obtain 23.8 mg (19% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] - [(1E) -2- (quinolin-5-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 18 mg (39 μmol) (1E, 6E) -1- [2-methoxy-4- (2 -pyridylmethoxy) phenyl] -7- (quinolin-5-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole-5 -yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 4.6 mg (26% yield) of the target compound in the form of a light yellowish white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.66 (dd, J = 2.4, 8.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.91 (s, 1H), 7.08 (d, J = 17 Hz, 1H), 7.28 (d, J = 17 Hz, 1H), 7.32 (dd, J = 5.7Hz, 1H), 7.41 (d, J = 17Hz, 1H), 7.52-7.58 (m, 3H), 7.77 (t , J = 7.9 Hz, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 17 Hz, 1H), 8.58 (broad d, J = 5 Hz, 1H), 8.82 (d, J = 8.5 Hz, 1H), 8.93 (dd, J = 1.6, 4.0 Hz, 1H). Melting point 107-120 ° C, MS (ESI +) m / z 461.2 (M + 1).

Example 70: Synthesis of 3 - [(1E) -2- (1-benzyl-1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1-benzyl-1H-indol-6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The synthesis was carried out in the same manner as in Example 30 (2), except that 32 mg (0.14 mmol) of 1-benzyl-1H-indole-6-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H -benzotriazole-5-carboxaldehyde, obtaining 32.1 mg (44% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1-benzyl-1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (37 μmol) (1E, 6E) -1- (1-benzyl-1H-indole- 6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) - [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 8.4 mg (42% yield) of the target compound in the form light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 5.21 (s, 2H), 5.49 (s, 2H), 6.50 (dd, J = 1, 3 Hz, 1H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.66 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.21-7.28 (m, 4H), 7.28-7.34 (m , 4H), 7.36 (d, J = 17 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.58 (br s, 1H), 7.82 (dt, J = 1 8.7.7 Hz, 1H); 8.58 (brd, J = 5 Hz, 1H). Melting point 89-93 ° C, MS (ESI +) m / z 539.2 (M + 1).

Example 71: Synthesis of 3 - [(1E) -2- [2-bromo-4- (morpholin-4-yl) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [2-bromo-4- (morpholin-4-yl) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3, 5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 36 mg (0.14 mmol) of 2-bromo-4- (morpholin-4-yl) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, to obtain 62.6 mg (98% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [2-bromo-4- (morpholin-4-yl) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 35 mg (74 μmol) (1E, 6E) -1- [2-bromo-4- (morpholine -4-yl) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H -indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 16.4 mg (47% yield) of the target compound in the form light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.20 (t, J = 5 Hz, 2H), 3.77 (t, J = 5 Hz, 2H), 6.46 (dd, J = 1, 3 Hz, 1H), 6.74 (s, 1H), 6.99 (d, J = 17 Hz, 1H), 7.00 (dd, J = 2.5, 8.4 Hz, 1H), 7 10 (d, J = 17 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.5, 8.4 Hz, 1H), 7.34 (m, 1H), 7.40 (d, J = 17 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H ), 7.58 (br s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 10.3 (br s, NH). Melting point 143-148 ° C, MS (ESI +) m / z 475.3 (M + 1).

Example 72: Synthesis of 3 - [(1E) -2- [2-bromo-4- (4-methyl-1,4-diazepan-1-yl) phenyl] ethenyl] -5 - [(1E) -2- ( 1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [2-bromo-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -7- (1H-indol-6-yl) hepta- 1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 40 mg (0.14 mmol) of 2-bromo-4- (4-methyl-1,4-diazepan-1-yl) benzaldehyde used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde to obtain 59.3 mg (87% yield) of the target compound in the form of a brown powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [2-bromo-4- (4-methyl-1,4-diazepan-1-yl) phenyl]] - 5 - [(1E) -2- (1H -indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 35 mg (70 μmol) (1E, 6E) -1- [2-bromo-4- (4) -methyl-1,4-diazepan-1-yl) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E , 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 7.0 mg (20% -th yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.96 (t, J = 5.6, 6.2 Hz, 2H), 2.30 (s, 3H), 2.50 (t, J = 5 6 Hz, 2H), 2.66 (t, J = 4.9 Hz, 2H), 3.50 (t, J = 6.2 Hz, 2H), 3.58 (t, J = 5.0 Hz, 2H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.70 (s, 1H), 6.79 (dd, J = 2.5, 8.9 Hz, 1H), 6.90 (d, J = 17 Hz, 1H), 6.91 (d, J = 2.6 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.31 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.3, 8 Hz, 1H), 7.34 (m, 1H), 7.39 (d, J = 17 Hz, 1H), 7 55 (d, J = 8.3 Hz, 1H), 7.57 (br s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 10.3 (br s, NH). Melting point 132-136 ° C, MS (ESI +) m / z 502.2 (M + 1).

Example 73: Synthesis of 3 - [(1E) -2- (1-acetyl-1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1-acetyl-1H-indol-6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 40 mg (0.21 mmol) of 1-acetyl-1H-indole-6-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde to give 25.0 mg (24% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1-acetyl-1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (40 mmol) (1E, 6E) -1- (1-acetyl-1H-indole- 6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione to give 9.6 mg (48% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.69 (s, 3H), 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3 , 8.5 Hz, 1H), 6.69 (dd, J = 1, 3.8 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.77 (s, 1H ), 7.06 (d, J = 17 Hz, 1H), 7.18 (d, J = 17 Hz, 1H), 7.31 (dd, J = 5.7 Hz, 1H), 7.35 ( d, J = 17 Hz, 1H), 7.39 (d, J = 17 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.53-7.58 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 3.8 Hz, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 8.60 (br s, 1H). Melting point 182-187 ° C, MS (ESI +) m / z 491.3 (M + 1).

Example 74: Synthesis of 3 - [(1E) -2- (1-methanesulfonyl-1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1-methanesulfonyl-1H-indol-6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 30 mg (0.13 mmol) of 1-methanesulfonyl-1H-indole-6-carboxaldehyde was used instead (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde, to obtain 14.1 mg (20% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- (1-methanesulfonyl-1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 12 mg (23 μmol) (1E, 6E) -1- (1-methanesulfonyl-1H-indole- 6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 4.6 mg (38% yield) of the target compounds in the form of a white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.38 (s, 3H), 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3 , 8.5 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.77 (s, 1H), 6.80 (dd, J = 1, 3.7 Hz, 1H ), 7.06 (d, J = 17 Hz, 1H), 7.21 (d, J = 17 Hz, 1H), 7.31 (dd, J = 5.7 Hz, 1H), 7.37 ( d, J = 17 Hz, 1H), 7.39 (d, J = 17 Hz, 1H), 7.51-7.57 (m, 3H), 7.58 (d, J = 1.3, 6 , 4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.04 (br s , 1H), 8.58 (brd, J = 5 Hz, 1H). Melting point 212-214 ° C, MS (ESI +) m / z 527.3 (M + 1).

Example 75: Synthesis of 3 - [(1E) -2- (7-aza-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (7-aza-1H-indol-3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 40 mg (0.27 mmol) of 7-aza-1H-indole-3-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde to give 78.4 mg (63% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (7-aza-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 30 mg (66 μmol) (1E, 6E) -1- (7-aza-1H-indole- 3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 18.0 mg (60% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3, 8 Hz, 1H), 6, 66 (s, 1H), 6.73 (d, J = 2.3 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.11 (d, J = 17 Hz, 1H) , 7.16 (dd, J = 4.7, 7.9 Hz, 1H), 7.31 (dd, J = 5, 7 Hz, 1H), 7.37 (d, J = 17 Hz, 1H) , 7.39 (d, J = 17 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.28 (dd, J = 1.5, 4.7 Hz, 1H), 8.35 ( dd, J = 1.5, 7.9 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 10.8 (br s, NH). Melting point 219-223 ° C, MS (ESI +) m / z 450.2 (M + 1).

Example 76: Synthesis of 3 - [(1E) -2- [4- [2- (dimethylamino) ethoxy] -2-methoxyphenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [4- [2- (dimethylamino) ethoxy] -2-methoxyphenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3, 5-dione

The synthesis was carried out in the same manner as in Example 16 (1), except that 31 mg (0.14 mmol) of 4- [2- (dimethylamino) ethoxy] -2-methoxybenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, to obtain 34.9 mg (59% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [4- [2- (dimethylamino) ethoxy] -2-methoxyphenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 25 mg (58 μmol) (1E, 6E) -1- [4- [2- (dimethylamino) ethoxy] -2-methoxyphenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H -indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 11.7 mg (47% yield) of the target compound in a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.25 (s, 6H), 2.67 (br t, J = 6 Hz, 1H), 3.89 (s, 3H), 4.11 ( t, J = 5.9 Hz, 1H), 5.22 (s, 2H), 6.45 (broad d, J = 3 Hz, 1H), 6.56 (dd, J = 2.3, 8 5 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.68 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 ( d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 Hz, 1H), 7.34 (m, 1H) , 7.37 (d, J = 17 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.57 (broad s, 1H); 10.3 (broad s, NH). Melting point 109-112 ° C, MS (ESI +) m / z 429.4 (M + 1).

Example 77: Synthesis of 3 - [(1E) -2- (1,3-benzodioxol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1,3-benzodioxol-5-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3, 5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 40 mg (0.27 mmol) of 1,3-benzodioxole-5-carboxaldehyde was used instead of 20 mg (0 , 14 mmol) of 1H-benzotriazole-5-carboxaldehyde, to obtain 23.8 mg (20% yield) of the target compound in the form of a brown powder.

(2) Synthesis of 3 - [(1E) -2- (1,3-benzodioxol-5-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (44 mmol) (1E, 6E) -1- (1,3-benzodioxol-5- il) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H -indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 3.6 mg (18% yield) of the target compound in the form yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.01 (s, 2H), 6.64 (dd, J = 2.4 , 8.6 Hz, 1H), 6.65 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 17 Hz, 1H), 7.00 (dd, J = 1.6, 8.0 Hz, 1H), 7.04 (d, J = 17 Hz, 1H), 7, 14 (d, J = 17 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 5, 7 Hz, 1H), 7.36 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.56 (wide d, J = 8.2 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H). Melting point 218-220 ° C, MS (ESI +) m / z 454.3 (M + 1).

Example 78: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-isopropylphenyl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- (4-isopropylphenyl) hepta-1,6-diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 16 (1), except that 20 mg (0.14 mmol) of 4-isopropylbenzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde to give 27.9 mg (57% yield) of the target compound in the form of a yellow powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- (4-isopropylphenyl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 30 mg (84 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- (4-isopropylphenyl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [ 4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 22.2 mg (74% yield) of the target compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.23 (d, J = 6.9 Hz, 6H), 2.90 (t, J = 6.9, 6.9 Hz, 1H), 6, 46 (dd, J = 1, 3 Hz, 1H), 6.74 (s, 1H), 7.10 (d, J = 17 Hz, 1H), 7.11 (d, J = 17 Hz, 1H) 7.18 (d, J = 17 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd , J = 1.4, 8 Hz, 1H), 7.34 (m, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.6 Hz , 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 208-212 ° C, MS (ESI +) m / z 354.2 (M + 1).

Example 79: Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (4-nitro-1H-indole-3- il) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (4-nitro-1H-indol-3-yl) hepta-1,6-diene 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 52 mg (0.27 mmol) of 4-nitro-1H-indole-3-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde to obtain 20.6 mg (15% yield) of the target compound in the form of a yellow powder.

(2) Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (4-nitro-1H-indole-3- il) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 15 mg (30 μmol) (1E, 6E) -1- [2-methoxy-4- (2 -pyridylmethoxy) phenyl] -7- (4-nitro-1H-indol-3-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 mmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione to give 7.8 mg (52% yield) of the target compound in the form of an orange powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.62 (s, 1H), 6.64 (dd, J = 2.3 , 8.6 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 17 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.31 (dd, J = 7.9, 8.0 Hz, 1H), 7.32 (m, 1H), 7.38 (d, J = 17 Hz, 1H), 7.49 ( d, J = 17 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.56 (brd, J = 7.8 Hz, 1H), 7.81 (dt, J = 1.7, 7.7 Hz, 1H), 7.81 (dd, J = 0.7, 7.9 Hz, 1H), 7.81 (dd, J = 0.7, 8.0 Hz , 1H), 8.02 (s, 1H), 8.58 (brd, J = 5 Hz, 1H), 11.3 (br s, NH). Melting point 125-131 ° C, MS (ESI +) m / z 494.3 (M + 1).

Example 80: Synthesis of 3 - [(1E) -2- [4- (cyclohexyl methoxy) -2-methoxyphenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H pyrazole

(1) Synthesis of (1E, 6E) -1- [4- (cyclohexylmethoxy) -2-methoxyphenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 16 (1), except that 67 mg (0.27 mmol) of 4- (cyclohexyl methoxy) -2-methoxybenzaldehyde was used instead of 29 mg ( 0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, to obtain 84.1 mg (70% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [4- (cyclohexylmethoxy) -2-methoxyphenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H- pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 30 mg (66 μmol) (1E, 6E) -1- [4- (cyclohexyl methoxy) -2 -methoxyphenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole-5 -yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 7.0 mg (23% yield) of the desired compound in the form of a light yellowish white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.02-1.38 (m, 6H), 1.64-1.92 (m, 5H), 3.83 (d, J = 6.3 Hz , 2H), 3.90 (s, 3H), 6.45 (broad d, J = 3 Hz, 1H), 6.54 (dd, J = 2.3, 8.5 Hz, 1H), 6 58 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 7.03 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H ), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8.2 Hz, 1H), 7.34 (m, 1H), 7.37 (d , J = 17 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.57 (br s, 1H ), 10.3 (br s, NH). Melting point 104-108 ° C, MS (ESI +) m / z 454.4 (M + 1).

Example 81: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- [2- (pyrrol-1-yl ) ethoxy] phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- [2- (pyrrol-1-yl) ethoxy] phenyl] hepta-1,6 -diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 16 (1), except that 66 mg (0.27 mmol) of 2-methoxy-4- [2- (pyrrol-1-yl) ) ethoxy] benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde to obtain 60.5 mg (50% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- [2- (pyrrol-1-yl ) ethoxy] phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 30 mg (66 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- [2- (pyrrol-1-yl) ethoxy] phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 14.7 mg (49% yield) ) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.88 (s, 3H), 4.31 (m, 4H), 6.01 (t, J = 2.1 Hz, 2H), 6.45 ( dd, J = 1, 3 Hz, 1H), 6.55 (dd, J = 2.3, 8.5 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6, 67 (s, 1H), 6.80 (t, J = 2.1 Hz, 2H), 7.04 (d, J = 17 Hz, 1H), 7.08 (d, J = 17 Hz, 1H) , 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 Hz, 1H), 7.34 (m, 1H), 7.36 (d, J = 17 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H), 10 , 3 (br s, NH). Melting point 102-110 ° C, MS (ESI +) m / z 451.4 (M + 1).

Example 82: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (1,3-thiazole-2- ilmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (1,3-thiazol-2-ylmethoxy) phenyl] hepta-1,6- diene 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 16 (1), except that 71 mg (0.27 mmol) of 2-methoxy-4- (1,3-thiazole-2- Ilmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde to obtain 52.6 mg (43% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (1,3-thiazole-2- ilmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 30 mg (66 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (1,3-thiazol-2-ylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) - 1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione to obtain 17.4 mg (58% yield) the desired compound in the form of a yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.29 (s, 2H), 6.45 (brd, J = 3 Hz, 1H), 6.68 ( s, 1H), 6.68 (dd, J = 2.4, 8.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 Hz, 1H) , 7.34 (m, 1H), 7.38 (d, J = 17 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8, 1 Hz, 1H), 7.57 (br s, 1H), 7.69 (br d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.0 Hz, 1H) 10.3 (br s, NH). Melting point 229-237 ° C, MS (ESI +) m / z 455.3 (M + 1).

Example 83: Synthesis of 3 - [(1E) -2- (1,4-benzodioxan-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1,4-benzodioxan-6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3, 5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 44 mg (0.27 mmol) of 1,4-benzodioxan-6-carboxaldehyde was used instead of 20 mg (0 , 14 mmol) of 1H-benzotriazole-5-carboxaldehyde, to give 25.0 mg (20% yield) of the target compound in the form of an orange powder.

(2) Synthesis of 3 - [(1E) -2- (1,4-benzodioxan-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (42 μmol) (1E, 6E) -1- (1,4-benzodioxan-6- il) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H -indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 7.7 mg (39% yield) of the target compound in the form light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 4.27 (s, 4H), 5.22 (s, 2H), 6.64 (dd, J = 2.4 8.5 Hz, 1H), 6.65 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 17 Hz, 1H), 7.00-7.05 (m, 2H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.31 (dd, J = 5.7 Hz, 1H), 7.36 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H) 7.56 (br d, J = 8 Hz, 1H), 7.81 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H). Melting point 153-155 ° C, MS (ESI +) m / z 468.3 (M + 1).

Example 84: Synthesis of 3 - [(1E) -2- [2-bromo-5- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [2-bromo-5- (2-pyridylmethoxy) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5- dion

The synthesis was carried out using the same materials in the same relative amounts as in Example 16 (1), except that 78 mg (0.27 mmol) of 2-bromo-5- (2-pyridylmethoxy) benzaldehyde was used instead of 29 mg (0.14 mmol) of 4- (2-pyridylmethoxy) benzaldehyde, to obtain 28.1 mg (21% yield) of the target compound in the form of a brown powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- [2-bromo-5- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 20 mg (40 μmol) (1E, 6E) -1- [2-bromo-5- (2 -pyridylmethoxy) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indole -5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 3.4 mg (17% yield) of the desired compound in the form of a light yellowish and white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.28 (s, 2H), 6.46 (brd, J = 3 Hz, 1H), 6.80 (s, 1H), 6.93 ( dd, J = 3.0, 8.8 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.20 (d, J = 17 Hz, 1H), 7.29-7, 38 (m, 4H), 7.44 (d, J = 17 Hz, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.58 (br s, 1H), 7.59 (br d, J = 8 Hz, 1H), 7.83 ( dt, J = 1.7, 7.7 Hz, 1H), 8.58 (brd, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 100-106 ° C, MS (ESI +) m / z 497.3 (M + 1).

Example 85: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] ethenyl] -1-phenyl-1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-tetrahydrofuranylmethoxy ) phenyl] ethenyl] -1-phenyl-1H-pyrazole

10 mg (22 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) was dissolved in 0.22 ml of toluene and 11 μl of trifluoroacetic acid. phenyl] hepta-1,6-diene-3,5-dione. 7.3 mg (66 μmol) of phenylhydrazine was added to this solution at room temperature, and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol). The resulting solid was washed with an organic solvent to obtain 3.1 mg (27% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (m, 4H), 3.71 (m, 1H), 3.83 (m, 1H), 3.88 (s, 3H × 0.5), 3.91 (s, 3H × 0.5), 3.99 (d, J = 5.3 Hz, 1H × 0.5), 4.00 (d, J = 5.3 Hz, 1H × 0.5), 4.2 (m, 1H), 6.45 (m, 1H), 6.53 (dd, J = 2.8 Hz, 1H × 0.5), 6.58 (dd, J = 2.4, 8.5 Hz, 1H × 0.5), 6.61 (d, J = 3 Hz, 1H × 0.5), 6.62 (d, J = 3 Hz, 1H × 0.5), 6.97 (d, J = 17 Hz, 1H × 0.5), 7.00 (d, J = 17 Hz, 1H × 0.5), 7.01 (s, 1H ), 7.08 (d, J = 17 Hz, 1H × 0.5), 7.12 (d, J = 17 Hz, 1H × 0.5), 7.23 (dd, J = 2, 8, 2 Hz, 1H × 0.5), 7.32-7.62 (m, 11H + 1H × 0.5), 10.3 (br s, NH). Melting point 90-95 ° C, MS (ESI +) m / z 518.2 (M + 1).

Example 86: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1-phenyl-1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy ) phenyl] ethenyl] -1-phenyl-1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 85 except that 10 mg (22 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [ 2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 10 mg (22 μmol) (1E, 6E) -1- (1H-indol-6-yl ) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 7.7 mg (66% yield) of the desired compound in the form of a light yellowish and white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.88 (s, 3H × 0.5), 3.92 (s, 3H × 0.5), 5.21 (s, 2H × 0.5) , 5.23 (s, 2H × 0.5), 6.46 (brd, J = 3 Hz, 1H), 6.62 (dd, J = 2.5, 8.7 Hz, 1H × 0 5), 6.66 (dd, J = 2.5, 8.7 Hz, 1H × 0.5), 6.73 (d, J = 3 Hz, 1H × 0.5), 6.74 ( d, J = 3 Hz, 1H × 0.5), 6.95 (d, J = 17 Hz, 1H × 0.5), 7.01 (br s, 1H), 7.02 (d, J = 17 Hz, 1H × 0.5), 7.09 (d, J = 17 Hz, 1H × 0.5), 7.13 (d, J = 17 Hz, 1H × 0.5), 7.23 (dd, J = 2.8 Hz, 1H × 0.5), 7.26-7.63 (m, 13H + 1H × 0.5), 7.82 (m, 1H), 8.57 (m , 1H), 10.3 (br s, NH). Melting point 96-104 ° C, MS (ESI +) m / z 525.0 (M + 1).

Example 87: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] ethenyl] -1-nitrophenyl-1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-tetrahydrofuranylmethoxy ) phenyl] ethenyl] -1-nitrophenyl-H-pyrazole

20 mg (45 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) were dissolved in 0.44 ml of toluene and 22 μl of trifluoroacetic acid phenyl] hepta-1,6-diene-3,5-dione. To this solution, 21 mg (0.14 mmol) of 4-nitrophenylhydrazine was added at room temperature, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol). The resulting solid was washed with an organic solvent to obtain 5.7 mg (23% yield) of the target compound in the form of a yellow powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (m, 4H), 3.73 (m, 1H), 3.85 (m, 1H), 3.93 (s, 3H × 0.5), 3.94 (s, 3H × 0.5), 4.02 (d, J = 5 Hz, 1H × 0.5), 4.03 (d, J = 5 Hz, 1H × 0.5), 4.2 (m, 1H), 6.49 (m, 1H), 6.57 (dd, J = 2.4, 8.5 Hz, 1H × 0.5), 6.60 (dd, J = 2.4, 8.5 Hz, 1H × 0.5), 6.65 (d, J = 2.5 Hz, 1H × 0.5), 6.66 (d, J = 2 , 5 Hz, 1H × 0.5), 7.10 (d, J = 17 Hz, 1H × 0.5), 7.11 (d, J = 17 Hz, 1H × 0.5), 7.12 (s, 1H), 7.16 (d, J = 17 Hz, 1H × 0.5), 7.17 (d, J = 17 Hz, 1H × 0.5), 7.34 (dd, J = 1.4, 8.4 Hz, 1H × 0.5), 7.39 (m, 1H), 7.41 (dd, J = 1.4, 8.4 Hz, 1H × 0.5), 7 , 45-7.61 (m, 4H), 7.65 (broad s, 1H × 0.5), 7.66 (wide s, 1H × 0.5), 7.94 (wide d, J = 9.2 Hz, 2H × 0.5), 7.95 (wide d, J = 9.2 Hz, 2H × 0.5), 8.47 (wide d, J = 9.2 Hz , 2H × 0.5), 8.48 (broad d, J = 9.2 Hz, 2H × 0.5), 10.4 (broad s, NH). Melting point 94-101 ° C, MS (ESI +) m / z 563.2 (M + 1).

Example 88: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1-nitrophenyl-1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy ) phenyl] ethenyl] -1-nitrophenyl-1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 87, except that 20 mg (44 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-Methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 20 mg (45 μmol) (1E, 6E) -1- (1H-indole-6- yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 20.5 mg (81% yield) of the target compound in yellow form powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.93 (s, 3H × 0.5), 3.94 (s, 3H × 0.5), 5.25 (s, 2H), 6.49 (m, 1H), 6.66 (dd, J = 2.4, 9 Hz, 1H × 0.5), 6.69 (dd, J = 2.4, 9 Hz, 1H × 0.5), 6.77 (d, J = 2.5 Hz, 1H × 0.5), 6.78 (d, J = 2.5 Hz, 1H × 0.5), 7.10 (d, J = 17 Hz , 1H × 0.5), 7.12 (d, J = 17 Hz, 1H × 0.5), 7.13 (br s, 1H), 7.16 (d, J = 17 Hz, 1H × 0.5), 7.17 (d, J = 17 Hz, 1H × 0.5), 7.30-7.42 (m, 3H), 7.45-7.54 (m, 2H), 7 , 54-7.67 (m, 3H), 7.65 (br s, 1H × 0.5), 7.66 (br s, 1H × 0.5), 7.83 (dt, J = 1.7, 7.8 Hz, 1H × 0.5), 7.84 (dt, J = 1.7, 7.8 Hz, 1H × 0.5), 7.94 (wide d, J = 9.2 Hz, 2H × 0.5), 7.95 (broad d, J = 9.2 Hz, 2H × 0.5), 8.46 (wide d, J = 9.2 Hz, 2H × 0.5), 8.48 (broad d, J = 9.2 Hz, 2H × 0.5), 8.60 (wide d, J = 6 Hz, 1H), 10.4 (wide s, NH). Melting point 107-112 ° C, MS (ESI +) m / z 570.2 (M + 1).

Example 89: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1-methyl-1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy ) phenyl] ethenyl] -1-methyl-1H-pyrazole

20 mg (44 μmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta- were dissolved in 0.22 ml of acetic acid 1,6-diene-3,5-dione. To this solution, 7.0 μl (0.13 mmol) of methylhydrazine was added at room temperature, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate or methylene chloride / methanol). The resulting solid was washed with an organic solvent to obtain 2.1 mg (10% yield) of the target compound in the form of a yellow powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.80 (s, 3H × 0.5), 3.90 (s, 3H × 0.5), 3.92 (s, 3H × 0.5) , 3.93 (s, 3H × 0.5), 5.22 (s, 2H × 0.5), 5.23 (s, 2H × 0.5), 6.44 (dd, J = 1, 3 Hz, 1H × 0.5), 6.46 (dd, J = 1.3 Hz, 1H × 0.5), 6.64 (dd, J = 2.3, 9 Hz, 1H × 0.5 ), 6.65 (dd, J = 2.3, 9 Hz, 1H × 0.5), 6.72 (d, J = 2.4 Hz, 1H × 0.5), 6.74 (br. s, 1H + 1H × 0.5), 6.98 (d, J = 17 Hz, 1H × 0.5), 7.02 (d, J = 17 Hz, 1H × 0.5), 7.09 (d, J = 17 Hz, 1H × 0.5), 7.12 (d, J = 17 Hz, 1H × 0.5), 7.26 (d, J = 17 Hz, 1H × 0.5) , 7.27-7.37 (m, 4H), 7.40 (dd, J = 1.3, 8.4 Hz, 1H × 0.5), 7.51-7.60 (m, 3H) , 7.63 (br s, 1H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H × 0.5), 7.82 (dt, J = 1.8, 7, 7 Hz, 1H × 0.5), 8.58 (broad d, J = 5 Hz, 1H), 10.28 (wide s, NH × 0.5), 10.33 (wide s, NH × 0.5). Melting point 80-85 ° C, MS (ESI +) m / z 463.1 (M + 1).

Example 90: Synthesis of 1-tert-butyl-3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2- pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole and 1-tert-butyl-5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2- methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 89 except that 16 mg (0.13 mmol) of tert-butyl hydrazine was used instead of 7.0 μl (0.13 mmol) of methyl hydrazine (reaction time was 14 hours), giving 2 , 5 mg (11% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.69 (s, 9H × 0.5), 1.71 (s, 9H × 0.5), 3.90 (s, 3H × 0.5) , 3.93 (s, 3H × 0.5), 5.22 (s, 2H × 0.5), 5.23 (s, 2H × 0.5), 6.44 (dd, J = 1, 3 Hz, 1H × 0.5), 6.46 (dd, J = 1.3 Hz, 1H × 0.5), 6.64 (dd, J = 2.5, 9 Hz, 1H × 0.5 ), 6.65 (dd, J = 2.5, 9 Hz, 1H × 0.5), 6.72 (d, J = 2.5 Hz, 1H × 0.5), 6.761 (d, J = 2.5 Hz, 1H × 0.5), 6.764 (br s, 1H), 6.99 (d, J = 17 Hz, 1H × 0.5), 7.04 (d, J = 17 Hz, 1H × 0.5), 7.17 (d, J = 17 Hz, 1H × 0.5), 7.22 (d, J = 17 Hz, 1H × 0.5), 7.26-7.38 (m, 4H + 1H × 0.5), 7.44 (d, J = 17 Hz, 1H × 0.5), 7.52-7.58 (m, 3H), 7.62 (br s , 1H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H × 0.5), 7.82 (dt, J = 1.8, 7.7 Hz, 1H × 0.5 ), 8.58 (broad d, J = 5 Hz, 1H), 10.25 (wide s, NH × 0.5), 10.31 (wide s, NH × 0.5). Melting point 76-84 ° C, MS (ESI +) m / z 505.3 (M + 1).

Example 91: Synthesis of 1-hydroxyethyl-3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole and 1-hydroxyethyl-5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 89 except that 9.0 μl (0.13 mmol) of 2-hydroxyethylhydrazine was used instead of 7.0 μl (0.13 mmol) of methylhydrazine (reaction time was 2 hours), receiving 10.2 mg (47% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.88-3.94 (m, 2H), 3.90 (s, 3H × 0.5), 3.91 (s, 3H × 0.5) , 4.31 (d, J = 5.6 Hz, 2H × 0.5), 4.34 (d, J = 5.6 Hz, 2H × 0.5), 5.22 (s, 2H × 0 5), 5.23 (s, 2H × 0.5), 6.45 (dd, J = 1.3 Hz, 1H × 0.5), 6.46 (dd, J = 1.3 Hz, 1H × 0.5), 6.64 (dd, J = 2.5, 9 Hz, 1H × 0.5), 6.66 (dd, J = 2.5, 9 Hz, 1H × 0.5) , 6.73 (d, J = 2.5 Hz, 1H × 0.5), 6.74 (d, J = 2.5 Hz, 1H × 0.5), 6.76 (br s, 1H ), 7.00 (d, J = 17 Hz, 1H × 0.5), 7.05 (d, J = 17 Hz, 1H × 0.5), 7.16 (d, J = 17 Hz, 1H × 0.5), 7.20 (d, J = 17 Hz, 1H × 0.5), 7.28 (d, J = 17 Hz, 1H × 0.5), 7.27-7.40 ( m, 4H + 1H × 0.5), 7.52-7.59 (m, 3H), 7.60 (d, J = 8.7 Hz, 1H × 0.5), 7.62 (br. s, 1H × 0.5), 7.82 (broad dt, J = 2.8 Hz, 1H), 8.58 (wide d, J = 5 Hz, 1H), 10.29 (wide s , NH × 0.5), 10.33 (br s, NH × 0.5). Melting point 94-97 ° C, MS (ESI +) m / z 493 (M + 1).

Example 92: Synthesis of 1-benzyl-3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole and 1-benzyl-5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 89 except that 21 mg (0.13 mmol) of benzylhydrazine was used instead of 7.0 μl (0.13 mmol) of methylhydrazine (reaction time was 10 hours), yielding 11.2 mg (47% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.88 (s, 3H × 0.5), 3.90 (s, 3H × 0.5), 5.21 (s, 2H × 0.5) , 5.22 (s, 2H × 0.5), 5.50 (s, 2H × 0.5), 5.54 (s, 2H × 0.5), 6.44 (m, 1H), 6 , 61 (dd, J = 2.3, 8.6 Hz, 1H × 0.5), 6.64 (dd, J = 2.4, 8.6 Hz, 1H × 0.5), 6.72 (d, J = 2.4 Hz, 1H × 0.5), 6.73 (d, J = 2.4 Hz, 1H × 0.5), 6.84 (br s, 1H), 7, 03 (d, J = 17 Hz, 1H × 0.5), 7.07 (d, J = 17 Hz, 1H × 0.5), 7.12 (d, J = 17 Hz, 1H × 0.5 ), 7.14 (d, J = 17 Hz, 1H × 0.5), 7.22-7.35 (m, 9H + 1H × 0.5), 7.39 (d, J = 17 Hz, 1H × 0.5), 7.47 (d, J = 8.7 Hz, 1H × 0.5), 7.51-7.57 (m, 2H + 1H × 0.5), 7.57 ( broad s, 1H × 0.5), 7.58 (broad s, 1H × 0.5), 7.81 (dt, J = 1.8, 7.7 Hz, 1H × 0.5), 7.82 (dt, J = 1.8, 7.7 Hz, 1H × 0.5), 8.57 (m, 1H), 10.29 (br s, NH × 0.5), 10, 32 (br s, NH × 0.5). Melting point 80-86 ° C, MS (ESI +) m / z 539.2 (M + 1).

Example 93: Synthesis of 1-cyclohexyl-3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole and 1-cyclohexyl-5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 89 except that 20 mg (0.13 mmol) of cyclohexyl hydrazine was used instead of 7.0 μl (0.13 mmol) of methylhydrazine (reaction time was 12 hours), giving 3, 6 mg (15% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 1.2-2.0 (m, 10H), 3.90 (s, 3H × 0.5), 3.92 (s, 3H × 0.5) , 4.43 (m, 1H), 5.22 (s, 2H × 0.5), 5.23 (s, 2H × 0.5), 6.44 (wide d, J = 3 Hz, 1H × 0.5), 6.46 (broad d, J = 3 Hz, 1H × 0.5), 6.65 (wide dd, J = 2, 9 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H × 0.5), 6.74 (br s, 1H), 6.75 (d, J = 2.4 Hz, 1H × 0.5), 7.02 (d , J = 17 Hz, 1H × 0.5), 7.06 (d, J = 17 Hz, 1H × 0.5), 7.16 (d, J = 17 Hz, 1H × 0.5), 7 , 20 (d, J = 17 Hz, 1H × 0.5), 7.25 (d, J = 17 Hz, 1H × 0.5), 7.27-7.38 (m, 4H), 7, 40 (dd, J = 1.3, 8.4 Hz, 1H × 0.5), 7.52-7.58 (m, 3H), 7.60 (d, J = 8.7 Hz, 1H × 0.5), 7.61 (br.s, 1H × 0.5), 7.81 (br.dt, J = 2, 8 Hz, 1H), 8.58 (br. D, J = 4 Hz , 1H), 10.29 (br s, NH × 0.5), 10.32 (br s, NH × 0.5). Melting point 101-115 ° C, MS (ESI +) m / z 531.3 (M + 1).

Example 94: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1- (2-pyridyl) -1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1- (2-pyridyl) -1H-pyrazole

The synthesis was carried out in the same manner as in Example 89 except that 15 mg (0.13 mmol) of 2-pyridylhydrazine was used instead of 7.0 μl (0.13 mmol) of methylhydrazine to obtain 18.2 mg (78% - yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.92 (s, 3H × 0.5), 3.93 (s, 3H × 0.5), 5.23 (s, 2H × 0.5) , 5.24 (s, 2H × 0.5), 6.47 (broad d, J = 3 Hz, 1H), 6.66 (dd, J = 2.5, 8.5 Hz, 1H × 0 5), 6.67 (dd, J = 2.3, 8.5 Hz, 1H × 0.5), 6.75 (d, J = 2 Hz, 1H × 0.5), 6.76 ( d, J = 2 Hz, 1H × 0.5), 7.11 (d, J = 17 Hz, 1H × 0.5), 7.102 (br s, 1H × 0.5), 7.106 (br s , 1H × 0.5), 7.14 (d, J = 17 Hz, 1H × 0.5), 7.30-7.61 (m, 9H), 7.63 (br s, 1H × 0 5), 7.64 (br s, 1H × 0.5), 7.818 (dt, J = 1.8, 7.7 Hz, 1H × 0.5), 7.822 (dt, J = 1.8 , 7.7 Hz, 1H × 0.5), 7.94-8.02 (m, 2H), 8.12 (d, J = 17 Hz, 1H × 0.5), 8.16 (d, J = 17 Hz, 1H × 0.5), 8.52-8.60 (m, 2H), 10.3 (br s, NH). Melting point 91-97 ° C, MS (ESI +) m / z 526.2 (M + 1).

Example 95: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1- (4-methoxyphenyl) -5 - [(1E) -2- [2-methoxy-4- ( 2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1- (4-methoxyphenyl) -3 - [(1E) -2 - [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 89 except that 23 mg (0.13 mmol) of 4-methoxyphenylhydrazine was used instead of 7.0 μl (0.13 mmol) of methylhydrazine to give 7.9 mg (32% - yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.888 (s, 3H × 0.5), 3.883 (s, 3H × 0.5), 3.90 (s, 3H × 0.5), 3.91 (s, 3H × 0.5), 5.21 (s, 2H × 0.5), 5.23 (s, 2H × 0.5), 6.45 (m, 1H), 6.61 (dd , J = 2.4, 8.5 Hz, 1H × 0.5), 6.66 (dd, J = 2.4, 8.5 Hz, 1H × 0.5), 6.73 (d, J = 3 Hz, 1H × 0.5), 6.74 (d, J = 3 Hz, 1H × 0.5), 6.88 (d, J = 17 Hz, 1H × 0.5), 6.94 (d, J = 17 Hz, 1H × 0.5), 6.97 (br s, 1H), 7.07 (d, J = 17 Hz, 1H × 0.5), 7.08-7, 14 (m, 2H + 1H × 0.5), 7.21 (dd, J = 1.4, 8.4 Hz, 1H × 0.5), 7.28-7.60 (m, 10H), 7.61 (br s, 1H × 0.5), 7.81 (dt, J = 1.7, 7.8 Hz, 1H × 0.5), 7.82 (dt, J = 1.8 , 7.8 Hz, 1H × 0.5), 8.57 (m, 1H), 10.3 (br s, NH). Melting point 92-99 ° C, MS (ESI +) m / z 555.1 (M + 1).

Example 96: Synthesis of 3 - [(1E) -2- (1H-indol-6-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1- (2-methylphenyl) -1H-pyrazole and 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1- (2-methylphenyl) -1H-pyrazole

The synthesis was carried out in the same manner as in Example 89, except that 21 mg (0.13 mmol) of 2-methylphenylhydrazine was used instead of 7.0 μl (0.13 mmol) of methylhydrazine to obtain 21.4 mg (74% -th yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 2.04 (s, 3H × 0.5), 2.10 (s, 3H × 0.5), 3.81 (s, 3H × 0.5) , 3.91 (s, 3H × 0.5), 5.18 (s, 2H × 0.5), 5.22 (s, 2H × 0.5), 6.43 (wide d, J = 3 Hz, 1H × 0.5), 6.45 (broad d, J = 3 Hz, 1H × 0.5), 6.56 (d, J = 17 Hz, 1H × 0.5), 6, 57 (dd, J = 2.4, 8.3 Hz, 1H × 0.5), 6.60 (d, J = 17 Hz, 1H × 0.5), 6.66 (dd, J = 2, 4, 8.6 Hz, 1H × 0.5), 6.69 (d, J = 2.4 Hz, 1H × 0.5), 6.74 (d, J = 2.3 Hz, 1H × 0 5), 6.99 (br s, 1H), 7.01 (d, J = 7.4 Hz, 1H × 0.5), 7.08 (d, J = 17 Hz, 1H × 0, 5), 7.11 (d, J = 7.4 Hz, 1H × 0.5), 7.12 (d, J = 17 Hz, 1H × 0.5), 7.26-7.61 (m , 12H), 7.79 (dt, J = 1.7, 7.8 Hz, 1H × 0.5), 7.82 (dt, J = 1.7, 7.8 Hz, 1H × 0.5 ), 8.56 (broad d, J = 5 Hz, 1H × 0.5), 8.57 (wide d, J = 5 Hz, 1H × 0.5), 10.27 (wide s, NH × 0.5), 10.31 (br s, NH × 0.5). Melting point 94-100 ° C, MS (ESI +) m / z 539.3 (M + 1).

Example 97: Synthesis of 3 - [(1E) -2- [4-diethylamino-2- [2- (1-piperidyl) ethoxy] phenyl] ethenyl] -5 - [(1E) -2- (1H-indole-6 -yl) ethenyl] -1H-pyrazole

(1) Synthesis of 4-diethylamino-2- [2- (1-piperidyl) ethoxy] benzaldehyde

2.8 g (14.6 mmol) of 4-diethylaminosalicylaldehyde were dissolved in 90 ml of acetonitrile. To this solution, 14.3 g (43.8 mmol) of cesium carbonate and 2.8 g (15.3 mmol) of 1- (2-chloroethyl) piperidine hydrochloride were added at room temperature, and the mixture was stirred at 80 ° C for 4 hours. Water (150 ml) was added to the resulting reaction mixture, and extraction was performed with ethyl acetate (100 ml × 3). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain quantitatively 4.5 g of the target compound.

¹ H NMR (δ, chloroform-d): 1.21 (t, J = 7.1 Hz, 6H), 1.43-1.48 (m, 2H), 1.59-1.64 (m, 4H), 2.52-2.58 (m, 4H), 2.83-2.86 (m, 2H), 3.39-3.44 (m, 4H), 4.17-4.21 ( m, 2H), 6.04 (d, J = 2.3 Hz, 1H), 6.28 (dd, J = 1.7 Hz, 9.0 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H); 10.16 (s, 1H). Melting point 70-72 ° C, MS (EI) m / z 304 (M +).

(2) Synthesis of (1E, 6E) -1- [4-diethylamino-2- [2- (1-piperidyl) ethoxy] phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene -3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 1 (2), except that 295 mg (0.97 mmol) of 4-diethylamino-2- [2- (1-piperidyl) ethoxy ] benzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy-4- (2-tetrahydrofuranylmethoxy) benzaldehyde to give 140 mg (31% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 1.14 (t, J = 7.1 Hz, 6H), 1.37-1.46 (m, 2H), 1.51-1.57 (m , 4H), 2.48-2.51 (m, 4H, overlapped DMSO), 2.73-2.76 (m, 2H), 3.40-3.45 (m, 4H), 4.15- 4.18 (m, 2H), 5.95 (s, 1H), 6.22 (d, J = 2.6 Hz, 1H), 6.33 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 6.46-6.48 (m, 1H), 6.65 (d, J = 15.4 Hz, 1H), 6.79 (d, J = 16.0 Hz, 1H), 7.37-7.40 (m, 1H), 7.45-7.48 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.65-7.69 ( m, 2H), 7.79 (d, J = 16.1 Hz, 1H), 11.31 (s, 1H), 16.61 (br s, 1H), MS (EI) m / z 513 ( M +).

(3) Synthesis of 3 - [(1E) -2- [4-diethylamino-2- [2- (1-piperidyl) ethoxy] phenyl] ethenyl] -5 - [(1E) -2- (1H-indole-6 -yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 400 mg (0.78 mmol) (1E, 6E) -1- [4-diethylamino-2- [2- (1-piperidyl) ethoxy]] - 7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) - 1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 196 mg (49% yield) of the target compound .

¹ H NMR (δ, DMSO-d ₆ ): 1.12 (t, J = 7.1 Hz, 6H), 1.37-1.44 (m, 2H), 1.52-1.58 (m , 4H), 2.52-2.59 (m, 4H), 2.76-2.82 (m, 2H), 3.35-3.40 (m, 4H), 4.12-4.16 (m, 2H), 6.24 (d, J = 2.6 Hz, 1H), 6.30 (dd, J = 2.3 Hz, 8.7 Hz, 1H), 6.42 (s, 1H ), 6.57 (s, 1H), 6.85 (d, J = 16.7 Hz, 1H), 7.00 (d, J = 16.6 Hz, 1H), 7.18-7.28 (m, 3H), 7.31-7.37 (m, 2H), 7.48-7.54 (m, 2H), 11.10 (s, 1H), 12.68 (br s, 1H ) Melting point 102-104 ° C, MS (EI) m / z 509 (M +).

Example 98: Synthesis of 3 - [(1E) -2- [4-diethylamino-2- (2-morpholinoethoxy) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of 4-diethylamino-2- (2-morpholinoethoxy) benzaldehyde

The synthesis was carried out using the same materials in the same relative amounts as in Example 97 (1), except that 5.1 g (27.2 mmol) of 1- (2-chloroethyl) morpholine hydrochloride was used instead of 2, 8 g (15.3 mmol) of 1- (2-chloroethyl) piperidine hydrochloride to give 7.0 g (89% yield) of the target compound.

¹ H NMR (δ, chloroform-d): 1.22 (t, J = 7.4 Hz, 6H), 2.58-2.63 (m, 4H), 2.85-2.88 (m, 2H), 3.39-3.45 (m, 4H), 3.71-3.75 (m, 4H), 4.18-4.21 (m, 2H), 6.03 (d, J = 2.3 Hz, 1H), 6.30 (dd, J = 1.8 Hz, 8.7 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 10.15 (s , 1H). Melting point 107-109 ° C, MS (EI) m / z 306 (M +).

(2) Synthesis of (1E, 6E) -1- [4-diethylamino-2- (2-morpholinoethoxy) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5- dion

The synthesis was carried out using the same materials in the same relative amounts as in Example 1 (2), except that 1.5 g (4.8 mmol) of 4-diethylamino-2- (2-morpholinoethoxy) benzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy-4- (2-tetrahydrofuranylmethoxy) benzaldehyde, yielding 1.2 g (53% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 1.14 (t, J = 6.8 Hz, 6H), 2.52-2.55 (m, 4H), 2.77-2.81 (m , 2H), 3.40-3.45 (m, 4H), 3.60-3.63 (m, 4H), 4.18-4.21 (m, 2H), 5.95 (s, 1H ), 6.23 (d, J = 2.6 Hz, 1H), 6.34 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 6.46-6.48 (m, 1H ), 6.66 (d, J = 15.3 Hz, 1H), 6.80 (d, J = 16.0 Hz, 1H), 7.38-7.41 (m, 1H), 7.44 -7.49 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.65-7.70 (m, 2H), 7.80 (d, J = 16.1 Hz, 1H), 11.31 (s, 1H), 16.62 (br s, 1H), MS (EI) m / z 515 (M +).

(3) Synthesis of 3 - [(1E) -2- [4-diethylamino-2- (2-morpholinoethoxy) phenyl]] - 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] - 1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 712 mg (1.38 mmol) (1E, 6E) -1- [4-diethylamino-2- (2-Morpholinoethoxy) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H -indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 446 mg (63% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 1.12 (t, J = 7.1 Hz, 6H), 2.53-2.58 (m, 4H), 2.78-2.83 (m , 2H), 3.34-3.40 (m, 4H), 3.60-3.63 (m, 4H), 4.14-4.18 (m, 2H), 6.25 (d, J = 1.9 Hz, 1H), 6.30 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 6.42 (s, 1H), 6.57 (s, 1H), 6, 87 (d, J = 16.7 Hz, 1H), 7.00 (d, J = 16.7 Hz, 1H), 7.18-7.28 (m, 3H), 7.31-7.36 (m, 2H), 7.49-7.54 (m, 2H), 11.10 (s, 1H), 12.69 (br s, 1H). Melting point 96-99 ° C, MS (EI) m / z 511 (M +).

Example 99: Synthesis of 3 - [(1E) -2- (5-fluoro-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (5-fluoro-1H-indol-3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 111 mg (0.68 mmol) of 5-fluoro-1H-indole-3-carbaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde to obtain 57 mg (20% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 3.89 (s, 3H), 5.26 (s, 2H), 6.11 (s, 1H), 6.69-6.78 (m, 4H ), 7.05-7.10 (m, 1H), 7.35-7.38 (m, 1H), 7.46-7.50 (m, 1H), 7.55 (d, J = 7 , 7 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 15.4 Hz, 1H), 7.80-7.88 (m, 3H ), 8.02 (s, 1H), 8.59-8.60 (m, 1H), 11.89 (s, 1H), 16.50 (br s, 1H). Melting point 183-186 ° C, MS (EI) m / z 470 (M +).

(2) Synthesis of 3 - [(1E) -2- (5-fluoro-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 40 mg (85 μmol) (1E, 6E) -1- (5-fluoro-1H-indole- 3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 20 mg (50% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.23 (s, 2H), 6.61-6.67 (m, 2H), 6.74 (s, 1H ), 6.90 (d, J = 16.7 Hz, 1H), 6.93-7.06 (m, 2H), 7.18-7.37 (m, 3H), 7.38-7, 44 (m, 1H), 7.47-7.56 (m, 2H), 7.60-7.64 (m, 1H), 7.69-7.71 (m, 1H), 7.85 ( dt, J = 1.9, 7.7 Hz, 1H), 8.58-8.60 (m, 1H), 11.30-11.47 (m, 1H), 12.55-12.75 ( m, 1H). Melting point 209-213 ° C, MS (EI) m / z 466 (M +).

Example 100: Synthesis of 3 - [(1E) -2- (5-methoxy-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (5-methoxy-1H-indol-3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 119 mg (0.68 mmol) of 5-methoxy-1H-indole-3-carbaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde to give 142 mg (48% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 3.89 (s, 3H), 5.26 (s, 2H), 6.08 (s, 1H), 6, 67-6.71 (m, 2H), 6.73-6.78 (m, 2H), 6.87 (dd, J = 2.3 Hz, 8.7 Hz, 1H), 7.35-7 38 (m, 2H), 7.42 (d, J = 2.6 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 8, 4 Hz, 1H), 7.74 (d, J = 16.1 Hz, 1H), 7.85 (dt, J = 1.9 Hz, 7.7 Hz, 1H), 7.88-7.93 (m, 2H), 8.59-8.60 (m, 1H), 11.70 (s, 1H), 16.58 (br s, 1H), MS (EI) m / z 482 (M +) .

(2) Synthesis of 3 - [(1E) -2- (5-methoxy-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 40 mg (83 μmol) (1E, 6E) -1- (5-methoxy-1H-indole- 3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 22 mg (55% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 3.84 (s, 3H), 3.86 (s, 3H), 5.22 (s, 2H), 6.61-6.68 (m, 2H ), 6.73 (s, 1H), 6.78-6.90 (m, 2H), 6.97 (d, J = 16.7 Hz, 1H), 7.20-7.72 (m, 8H), 7.85 (dt, J = 1.9, 7.7 Hz, 1H), 8.58-8.60 (m, 1H), 11.07-11.24 (m, 1H), 12 63-12.72 (m, 1H). Melting point 189-195 ° C, MS (EI) m / z 478 (M +).

Example 101: Synthesis of 3 - [(1E) -2- (5-benzyloxy-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (5-benzyloxy-1H-indol-3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 30 (2), except that 170 mg (0.67 mmol) of 5-benzyloxyindole-3-carboxaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde to obtain 94 mg (27% yield) of the target compound.

¹ H NMR (δ, DMSO-d ₆ ): 3.88 (s, 3H), 5.21 (s, 2H), 5.26 (s, 2H), 6.07 (s, 1H), 6, 66 (d, J = 16.0 Hz, 1H), 6.70 (dd, J = 2.2 Hz, 8.7 Hz, 1H), 6.73-6.78 (m, 2H), 6, 95 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 7.32-7.44 (m, 5H), 7.52-7.55 (m, 4H), 7.64 (d , J = 9.0 Hz, 1H), 7.74 (d, J = 16.1 Hz, 1H), 7.83-7.92 (m, 3H), 8.58-8.60 (m, 1H), 11.71 (s, 1H), 16.58 (br s, 1H), MS (EI) m / z 558 (M +).

(2) Synthesis of 3 - [(1E) -2- (5-benzyloxy-1H-indol-3-yl) ethenyl] -5 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 100 mg (0.18 mmol) (1E, 6E) -1- (5-benzyloxy-1H- indol-3-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) - 1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 42 mg (43% yield) of the target compound .

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.17 (s, 2H), 5.22 (s, 2H), 6.61-6.68 (m, 2H ), 6.73 (s, 1H), 6.84-6.92 (m, 2H), 6.98 (d, J = 16.0 Hz, 1H), 7.21-7.37 (m, 5H), 7.39-7.43 (m, 2H), 7.46-7.72 (m, 6H), 7.84 (dt, J = 1.9, 7.7 Hz, 1H), 8 59-8.60 (m, 1H); 11.10-11.26 (m, 1H); 12.63-12.72 (m, 1H); MS (EI) m / z 554 (M +).

Example 102: Synthesis of 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [4- (4-methylpiperazin-1-yl) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (4-methylpiperazin-1-yl) phenyl] hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 1 (2), except that 0.45 g (2.2 mmol) of 4- (4-methylpiperazin-1-yl) benzaldehyde was used instead of 20 mg (85 μmol) 2-methoxy-4- (2-tetrahydrofuranylmethoxy) benzaldehyde, yielding 0.47 g (52% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 2.22 (s, 3H), 2.42-2.45 (m, 4H), 3.25-3.33 (m, 4H, overlapped H2O), 6.09 (s, 1H), 6.46-6.49 (m, 1H), 6.68 (d, 1H, J = 16.09 Hz), 6.82 (d, 1H, J = 16, 0 Hz), 6.97 (d, 2H, J = 9.0 Hz), 7.41 (dd, 1H, J = 1.3 Hz, 8.4 Hz), 7.46-7.48 (m, 1H), 7.52-7.60 (m, 4H), 7.68-7.76 (m, 2H), 11.33 (s, 1H), 15.7-17.1 (br, 1H ) Melting point 65-77 ° C, MS (EI) m / z 413 (M ⁺ ).

(2) Synthesis of 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [4- (4-methylpiperazin-1-yl) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 0.45 g (1.09 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (4-methylpiperazin-1-yl) phenyl] hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indole-6- il) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 175 mg (39% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 2.22 (s, 3H), 2.43-2.47 (m, 4H), 3.15-3.21 (m, 4H), 6.42 (s, 1H), 6.67 (s, 1H), 6.81-7.13 (m, 5H), 7.16-7.31 (m, 2H), 7.32-7.43 (m , 3H), 7.49-7.57 (m, 1H), 7.50 (s, 1H), 11.10 and 11.12 (each s, total 1H), 12.78 and 12.79 (each s, total 1H). Melting point 192-198 ° C, MS (EI) m / z 409 (M ⁺ ).

Example 103: Synthesis of 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- (4-morpholinophenyl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- (4-morpholinophenyl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 1 (2), except that 0.42 g (2.2 mmol) of 4-morpholinobenzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy-4- (2- tetrahydrofuranylmethoxy) benzaldehyde to obtain 0.60 g (68% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.22-3.28 (m, 4H), 3.72-3.76 (m, 4H), 6.10 (s, 1H), 6.47 -6.49 (m, 1H), 6.70 (d, 1H, J = 16.0 Hz), 6.83 (d, 1H, J = 16.0 Hz), 6.98 (d, 2H, J = 9.0 Hz), 7.41 (dd, 1H, J = 1.3 Hz, 8.4 Hz), 7.45-7.48 (m, 1H), 7.53-7.61 (m , 4H), 7.69-7.71 (m, 1H), 7.73 (d, 1H, J = 16.0 Hz), 11.34 (s, 1H), 15.82-17.02 ( broad., 1H). Melting point 93-97 ° C, MS (EI) m / z 400 (M ⁺ ).

(2) Synthesis of 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) - (4-morpholinophenyl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 0.50 g (1.25 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- (4-morpholinophenyl) hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) - [2-methoxy-4 - (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 0.26 g (53% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.12-3.17 (m, 4H), 3.72-3.76 (m, 4H), 6.42 (s, 1H), 6.68 (s, 1H), 6.83-7.13 (m, 3H), 6.94 (d, 2H, J = 7.7 Hz), 7.17-7.39 (m, 3H), 7, 42 (d, 2H, J = 7.7 Hz), 7.49-7.56 (m, 1H), 7.51 (s, 1H), 11.05-11.17 (m, 1H), 12 80 (s, 1H). Melting point 236-238 ° C, MS (EI) m / z 396 (M ⁺ ).

Example 104: Synthesis of 3 - [(1E) -2- (4-diethylamino-2-methoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (4-diethylamino-2-methoxyphenyl) -7- (1H-indole-6-) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 1 (2), except that 0.46 g (2.2 mol) of 4- (diethylamino) -2-methoxybenzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy -4- (2-tetrahydrofuranylmethoxy) benzaldehyde to give 0.68 g (75% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.14 (t, 6H, J = 7.1 Hz), 3.40-3.46 (m, 4H), 3.88 (s, 3H), 5.99 (s, 1H), 6.20 (d, 1H, J = 1.9 Hz), 6.34 (dd, 1H, J = 2.6Hz, 9.0 Hz), 6.46-6 48 (m, 1H), 6.58 (d, 1H, J = 16.0 Hz), 6.81 (d, 1H, J = 16.0 Hz), 7.39 (dd, 1H, J = 1.3 Hz, 8.3 Hz), 7.44-7.47 (m, 1H), 7.50 (d, 1H, J = 9.0 Hz), 7.58 (d, 1H, J = 8 , 3 Hz), 7.66-7.68 (m, 1H), 7.68 (d, 1H, J = 16.0 Hz), 7.81 (d, 1H, J = 16.0 Hz), 11.31 (s, 1H); 16.00-17.20 (br, 1H). Melting point 61-65 ° C, MS (EI) m / z 416 (M ⁺ ).

(2) Synthesis of 3 - [(1E) -2- (4-diethylamino-2-methoxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 0.59 g (1.42 mmol) of (1E, 6E) -1- (4-diethylamino-2-methoxyphenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 55 mg (9.4% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.12 (t, 6H, J = 7.1 Hz), 3.38 (q, 4H, J = 7.1 Hz), 3.85 (s , 3H), 6.23 (br s, 1H), 6.27-6.33 (m, 1H), 6.40-6.43 (m, 1H), 6.62 (s, 1H), 6.82 (d, 1H, J = 16.7 Hz), 6.99 (d, 1H, J = 16.1 Hz), 7.19-7.28 (m, 3H), 7.32-7 38 (m, 2H), 7.49-7.51 (m, 1H), 7.52 (d, 1H, J = 8.4 Hz), 11.10 (s, 1H), 12.27- 13.07 (br., 1H). Melting point 104-108 ° C, MS (EI) m / z 412 (M ⁺ ).

Example 105: Synthesis of 3 - [(1E) -2- (4-dimethylaminophenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (4-dimethylaminophenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 1 (2), except that 0.33 g (2.2 mol) of 4-dimethylaminobenzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy-4- (2- tetrahydrofuranylmethoxy) benzaldehyde to give 0.63 g (36% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 3.00 (s, 6H), 6.07 (s, 1H), 6.47-6.48 (m, 1H), 6.62 (d, 1H , J = 16.0 Hz), 6.74 (d, 2H, J = 9.0 Hz), 6.81 (d, 1H, J = 16.0 Hz), 7.40 (dd, 1H, J = 1.3 Hz, 8.3 Hz), 7.45-7.48 (m, 1H), 7.55 (d, 2H, J = 9.0 Hz), 7.56 (d, 1H, J = 16.0 Hz), 7.58 (d, 1H, J = 8.3 Hz), 7.68-7.70 (m, 1H), 7.71 (d, 1H, J = 16.0 Hz) 11.33 (s, 1H); 15.70 - 17.20 (broad, 1H). Melting point 112-119 ° C, MS (EI) m / z 358 (M ⁺ ).

(2) Synthesis of 3 - [(1E) -2- (4-dimethylaminophenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 243 mg (0.68 mmol) (1E, 6E) -1- (4-dimethylaminophenyl) -7- (1H-indole-6 -yl) hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4 - (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 66 mg (28% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 2.93 (s, 6H), 6.42 (s, 1H), 6.66 (s, 1H), 6.73 (d, 2H, J = 8 , 3 Hz), 6.75-6.91 (m, 1H), 6.94-7.10 (m, 2H), 7.14-7.31 (m, 2H), 7.32-7, 41 (m, 1H), 7.38 (d, 2H, J = 8.3 Hz), 7.49-7.51 (m, 1H), 7.53 (d, 1H, J = 7.1 Hz ), 11.04-11.07 (m, 1H), 12.68-12.80 (m, 1H). Melting point 224-227 ° C, MS (EI) m / z 354 (M ⁺ ).

Example 106: Synthesis of 3 - [(1E) -2- (4-diethylaminophenyl) ethenyl] -5 - [(1E) -2- (1H-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (4-diethylaminophenyl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 1 (2), except that 0.39 g (2.2 mol) of 4-diethylaminobenzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy-4- (2- tetrahydrofuranylmethoxy) benzaldehyde to give 0.63 g (37% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.12 (t, 6H, J = 7.1 Hz), 3.41 (q, 4H, J = 7.1 Hz), 6.06 (s , 1H), 6.46-6.49 (m, 1H), 6.57 (d, 1H, J = 16.0 Hz), 6.70 (d, 2H, J = 9.0 Hz), 6 81 (d, 1H, J = 16.0 Hz), 7.40 (d, 1H, J = 8.3 Hz), 7.45-7.47 (m, 1H), 7.51 (d, 2H, J = 9.0 Hz), 7.54 (d, 1H, J = 16.0 Hz), 7.58 (d, 1H, J = 8.3 Hz), 7.68-7.73 ( m, 2H), 11.33 (s, 1H), 15.68-17.27 (br., 1H). Melting point 110-118 ° C, MS (EI) m / z 386 (M ⁺ ).

(2) Synthesis of 3 - [(1E) -2- (4-diethylaminophenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 264 mg (0.68 mmol) of (1E, 6E) -1- (4-diethylaminophenyl) -7- (1H-indole-6 -yl) hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4 - (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 112 mg (43% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.10 (t, 6H, J = 7.1 Hz), 3.36 (q, 4H, J = 7.1 Hz), 6.42 (s , 1H), 6.65 (s, 1H), 6.66 (d, 2H, J = 8.3 Hz), 6.71-6.88 (m, 1H), 6.93-7.09 ( m, 2H), 7.15-7.30 (m, 1H), 7.27 (d, 1H, J = 8.3 Hz), 7.32-7.38 (m, 3H), 7.50 (s, 1H), 7.53 (d, 1H, J = 8.3 Hz), 11.10 (s, 1H), 12.72 (s, 1H). Melting point 201-204 ° C, MS (EI) m / z 382 (M ⁺ ).

Example 107: Synthesis of 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [4- (1-piperidinyl) phenyl] ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (1-piperidinyl) phenyl] hepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 1 (2), except that 0.42 g (2.2 mol) of 4- (1-piperidinyl) benzaldehyde was used instead of 20 mg (85 μmol) of 2-methoxy -4- (2-tetrahydrofuranylmethoxy) benzaldehyde to give 0.65 g (74% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.56-1.62 (m, 6H), 3.23-3.34 (m, 4H, overlapped H2O), 6.08 (s, 1H), 6.47-6.49 (m, 1H), 6.65 (d, 1H, J = 16.0 Hz), 6.82 (d, 1H, J = 16.0 Hz), 6.94 (d , 2H, J = 9.0 Hz), 7.41 (dd, 1H, J = 1.3Hz, 8.4 Hz), 7.46-7.48 (m, 1H), 7.52-7, 60 (m, 4H), 7.68-7.71 (m, 1H), 7.73 (d, 1H, J = 16.0 Hz), 11.33 (s, 1H), 15.94-17 05 (br. 1H). Melting point 91-96 ° C, MS (EI) m / z 398 (M ⁺ ).

(2) Synthesis of 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -3 - [(1E) -2- [4- (1-piperidinyl) phenyl] ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 580 mg (1.46 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [4 - (1-piperidinyl) phenyl] hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [ 2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 144 mg (25% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.52-1.58 (m, 2H), 1.58-1.64 (m, 4H), 3.16-3.22 (m, 4H) , 6.40-6.44 (m, 1H), 6.67 (s, 1H), 6.79-7.10 (m, 3H), 6.92 (d, 2H, J = 9.0 Hz ), 7.16-7.30 (m, 1H), 7.26 (d, 1H, J = 7.7 Hz), 7.31-7.41 (m, 3H), 7.49-7, 51 (m, 1H), 7.53 (d, 1H, J = 7.7 Hz), 11.10 (s, 1H), 12.77 (s, 1H). Melting point 189-191 ° C, MS (EI) m / z 394 (M ⁺ ).

Example 108: Synthesis of 3 - [(1E) -2- [4-diethylamino-2- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of 4-diethylamino-2- (2-pyridylmethoxy) benzaldehyde

The synthesis was carried out using the same materials in the same relative amounts as in Example 97 (1), except that 1.8 g (10.9 mmol) of 2-chloromethylpyridine hydrochloride was used instead of 2.8 g (15, 3 mmol) 1- (2-chloroethyl) piperidine hydrochloride, quantitatively obtaining 2.9 g of the target compound.

¹ H NMR (δ, chloroform-d): 1.16 (t, J = 7.1 Hz, 6H), 3.36-3.41 (m, 4H), 5.38 (s, 2H), 6 , 13 (d, J = 2.3 Hz, 1H), 6.31 (dd, J = 2.1 Hz, 9.0 Hz, 1H), 7.30-7.33 (m, 1H), 7 70-7.74 (m, 2H), 7.81-7.85 (m, 1H), 8.59-8.61 (m, 1H), 10.26 (s, 1H). Melting point 78-81 ° C, MS (EI) m / z 284 (M +).

(2) Synthesis of (1E, 6E) -1- [4-diethylamino-2- (2-pyridylmethoxy) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5- dion

The synthesis was carried out in the same manner as in Example 1 (2), except that 0.39 g (1.4 mmol) of 4-diethylamino-2- (2-pyridylmethoxy) benzaldehyde was used instead of 20 mg (85 μmol) 2-methoxy-4- (2-tetrahydrofuranylmethoxy) benzaldehyde to give 0.68 g (90% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.05 (t, 6H, J = 7.1 Hz), 3.36 (q, 4H, J = 7.1 Hz), 5.33 (s , 2H), 5.96 (s, 1H), 6.25 (d, 1H, J = 2.6 Hz), 6.34 (dd, 1H, J = 2.6 Hz, 9.0 Hz), 6 , 46-6.48 (m, 1H), 6.66 (d, 1H, J = 16.0 Hz), 6.81 (d, 1H, J = 16.0 Hz), 7.35-7, 39 (m, 1H), 7.40 (dd, 1H, J = 1.3 Hz, 8.3 Hz), 7.44-7.47 (m, 1H), 7.51-7.55 (m, 2H), 7.58 (d, 1H, J = 8.3 Hz), 7.66-7.71 (m, 2H), 7.86-7.93 (m, 2H), 8.60-8 63 (m, 1H), 11.32 (s, 1H), 16.00-17.20 (br, 1H). Melting point 92-96 ° C, MS (EI) m / z 493 (M ⁺ ).

(3) Synthesis of 3 - [(1E) -2- [4-diethylamino-2- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 1 (3), except that 280 mg (0.57 mmol) of (1E, 6E) -1- [4-diethylamino-2- (2-pyridylmethoxy) phenyl] -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 400 mg (0.898 mmol) (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 24 mg (8.6% yield) of the target compound with the following properties.

¹ H NMR (δ, DMSO-d ₆ ): 1.03 (t, 6H, J = 7.7 Hz), 3.30 (t, 4H, J = 7.7 Hz), 5.29 (s, 2H), 6.23-6.26 (m, 1H), 6.27-6.32 (m, 1H), 6.41-6.43 (m, 1H), 6.61 (s, 1H) 6.87 (d, 1H, J = 16.7 Hz), 7.00 (d, 1H, J = 16.7 Hz), 7.20-7.41 (m, 6H), 7.48- 7.52 (m, 1H), 7.52 (d, 1H, J = 8.4 Hz), 7.55-7.59 (m, 1H), 7.87 (dt, 1H, J = 1, 9Hz, 7.7Hz), 8.58-8.62 (m, 1H), 11.10 (s, 1H), 12.33-13.13 (br, 1H). MS (EI) m / z 489 (M ⁺ ).

Example 109: Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2-phenylethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7-phenylhepta-1,6-diene-3,5-dione

The synthesis was carried out in the same manner as in Example 30 (2), except that 15 mg (0.14 mmol) of benzaldehyde was used instead of 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde to give 3, 9 mg (7% yield) of the target compound.

(2) Synthesis of 3 - [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -5 - [(1E) -2-phenylethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 13 mg (31 μmol) (1E, 6E) -1- [2-methoxy- (2-pyridylmethoxy) phenyl] -7-phenylhept -1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 8.6 mg (67% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.22 (s, 2H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.71 (s, 1H), 6.74 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.23 (d, J = 17 Hz, 1H), 7.22-7.42 (m, 5H), 7.53 (d, J = 8.5 Hz, 1H), 7.54-7.59 (m, 2H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H); 8.58 (brd, J = 5 Hz, 1H). Melting point 143-146 ° C, MS (ESI +) m / z 410.2 (M + 1).

Example 110: Synthesis of 3,5-bis [(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole

An amount of 149 mg (1E, 6E) -1,7-bis [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was obtained as a by-product in Example 30 (1 )

The synthesis was then carried out in the same manner as in Example 4 (4), except that 27.5 mg (50.0 μmol) (1E, 6E) -1,7-bis [2-methoxy-4- ( 2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, yielding 3.0 mg (13% yield) of the target compound in the form of a light yellowish-white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 5.22 (s, 4H), 6.63 (s, 1H), 6.68 (dd, J = 2.4, 8.3 Hz, 2H), 6.73 (d, J = 2.4 Hz, 2H), 7.05 (d, J = 17 Hz, 2H), 7.31 (m, 2H), 7.37 (d, J = 17 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.56 (m, 2H), 7.82 (dt, J = 1.7, 7.7 Hz, 2H), 8, 58 (broad d, J = 5 Hz, 2H). Melting point 195-197 ° C, MS (ESI +) m / z 547.3 (M + 1).

Example 111: Synthesis of 3 - [(1E) -2- (3-amino-4-hydroxyphenyl) ethenyl] -5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

(1) Synthesis of (1E, 6E) -1- (benzoxazol-5-yl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione

The synthesis was carried out using the same materials in the same relative amounts as in Example 16 (1), except that 40 mg (0.27 mmol) of benzoxazole-5-carboxaldehyde was used instead of 29 mg (0.14 mmol) 4- (2-pyridylmethoxy) benzaldehyde, to obtain 10.1 mg (8% yield) of the target compound in the form of an orange powder with the following properties.

(2) Synthesis of 3 - [(1E) -2- (3-amino-4-hydroxyphenyl)] - 5 - [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out using the same materials in the same relative amounts as in Example 4 (4), except that 8.0 mg (18 μmol) (1E, 6E) -1- (benzoxazol-5-yl) -7- (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione, obtaining 3.4 mg (44% yield) of the target compound in the form of a white powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 5.21 (s, 2H), 6.61 (s, 1H), 6.64 (dd, J = 2.2 , 8.5 Hz, 1H), 6.66 (dd, J = 1.7, 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.73 (d, J = 2 Hz, 1H), 6.85 (d, J = 17 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 7.02 (d, J = 17 Hz, 1H), 7 , 03 (d, J = 17 Hz, 1H), 7.31 (dd, J = 5, 7 Hz, 1H), 7.35 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.56 (broad d, J = 7.8 Hz, 1H), 7.81 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (broad d, J = 5 Hz, 1H). Melting point 123-126 ° C, MS (ESI +) m / z 441.3 (M + 1).

Example 112: Synthesis of 3,5-bis [(1E) -2- (1H-indol-6-yl) ethenyl] -1H-pyrazole

The synthesis was carried out in the same manner as in Example 4 (4), except that 17.7 mg (50.0 μmol) (1E, 6E) -1,7-bis (1H-indol-6-yl) hepta-1,6-diene-3,5-dione was used instead of 15 mg (35 μmol) (1E, 6E) -1- (1H-indol-5-yl) -7- [4- (2-pyridylmethoxy) phenyl ] hepta-1,6-diene-3,5-dione, obtaining 9.2 mg (53% yield) of the target compound in the form of a brown powder with the following properties.

¹ H NMR (δ, acetone-d ₆ ): 6.46 (dd, J = 0.9, 3.1 Hz, 2H), 6.74 (s, 1H), 7.10 (d, J = 17 Hz, 2H), 7.30 (d, J = 17 Hz, 2H), 7.32 (d, J = 1.6, 8.4 Hz, 2H), 7.35 (d, J = 3.1 Hz, 2H), 7.56 (d, J = 8 Hz, 2H), 7.57 (br s, 2H), 10.3 (br s, 2NH). Melting point 289-291 ° C, MS (ESI +) m / z 351.1 (M + 1).

Pharmacological Test Example 1: Determination of Tau Aggregation Inhibitory Activity

The recombinant microtubule binding domain with three repeats (3R-MBD) of the tau protein was expressed in E. coli, purified and used for the experiment. The purified tau solution was diluted with 50 mM Tris-HCl buffer (pH 7.6) to a final concentration of 10 μM. Test compounds were prepared using dimethyl sulfoxide (DMSO) at a 20-fold concentration relative to their final concentrations and added to the plate so that the DMSO concentration was 5%. Heparin was added to the plate so that the final concentration was 10 μM, and the plate was left at 37 ° C for 16 hours. Thioflavin T was added to the plate so that the concentration was 10 μM, and the fluorescence intensity was measured by a fluorescence spectrophotometer on tablets (PerkinElmer, Inc) (excitation wavelength: 440 nm; emission wavelength: 480 nm).

The final concentration of each compound during the measurement was set to 0.1, 0.3, 1, 3, and 10 μM. A sample to which only DMSO was added was used as a negative control, and its fluorescence intensity was taken as 0% inhibitory activity. The inhibitory activity of each compound was defined as a 50% inhibitory concentration (IC ₅₀ ). The test results are shown in Table 1. The inhibitory activities at 1 μM of the compounds of Example 109, Example 110, and Example 112 were 0%, 0%, and 24%, respectively.

Some of the samples that were left 16 hours after heparin addition were observed using an electron microscope. Samples were placed on a grid and washed with distilled water. A 1 mM aqueous solution of phosphoric tungsten acid was added to the samples. Samples were washed, dried overnight, and observed. The results are shown in FIG. 1. Samples to which the compound of Example 2 was added showed less tau aggregate formation and greater tau aggregation inhibitory activity than a sample to which only DMSO was added.

Pharmacological Test Example 2: Determination of β-secretase Inhibitory Activity

Inhibitory activity against β-secretase was measured using the FRET BACE-1 test kit (Invitrogen). Test compounds were prepared using DMSO at a 30-fold concentration relative to their final concentrations, and dissolved so that the DMSO concentration was 10%. An equal volume of recombinant human β-secretase (1 U / μl) dissolved in the test buffer was added to each of the solutions, and an equal volume of the fluorescent peptide substrate (2.5 nM) was added, and the solutions were left for 1 hour. The fluorescence intensity was measured by a spectrophotometer for measuring fluorescence on tablets (excitation wavelength: 545 nm; emission wavelength: 590 nm).

The final concentration of each compound during the measurement was set to 0.1, 0.3, 1, 3, and 10 μM, 0.3, 1, 3, 10, and 30 μM, or 1, 3, 10, 30, and 100 μM. A sample to which only DMSO was added was used as a negative control, and its fluorescence intensity was taken as 0% inhibitory activity to determine the 50% inhibitory concentration (IC ₅₀ ) of each compound. The fluorescent peptide substrate had the amino acid sequence Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Lys-Arg, in which the Ser residue at position 1 was labeled with a fluorescent donor (Cy3), and Lys at position 9 was labeled with a fluorescence quencher (Cy5Q). A 50% inhibitory concentration (IC ₅₀ ) of each compound was calculated. The test results are shown in Table 1. The inhibitory activities at 1 μM of the compounds of Example 109, Example 110, and Example 112 were 12%, 12%, and 30%, respectively.

Pharmacological Test Example 3: Determination of Aβ Aggregation Inhibitory Activity

Aβ 1-42 (Peptide Institute, Inc) was dissolved in a 0.3% aqueous ammonia solution so that the concentration was 0.5 mM, and then diluted with PBS to 20 μM. Test compounds were prepared using DMSO at 100-fold concentration with respect to their final concentrations and the concentration was adjusted so that the DMSO concentration was 2%. The Aβ solution and each of the solutions of the test compounds were mixed in an equivalent ratio, and the mixtures were incubated at 37 ° C for 24 hours. An equal volume of thioflavin T solution, adjusted with 100 mM Tris-glycine buffer (pH 8.5) to 6 μM, was added to each of the mixtures. The fluorescence intensity was measured by a spectrophotometer for measuring fluorescence on tablets (excitation wavelength: 440 nm; emission wavelength: 480 nm).

The final concentration of each compound during the measurement was set to 0.1, 0.3, 1, 3, and 10 μM. A sample to which only DMSO was added was used as a negative control, and its fluorescence intensity was taken as 0% inhibitory activity. Using the fluorescence intensity of the control, taken as 0% inhibitory activity, the 50% inhibitory concentration (IC ₅₀ ) of each compound was calculated. The test results are shown in Table 1. The inhibitory activity at 3 μM of the compound of Example 112 was 17%.

As shown above, compounds with the structure represented

by general formula (I), showed significantly superior effects in terms of at least one of the inhibitory activity against tau protein aggregation, inhibitory activity against β-secretase and inhibitory activity against Aβ aggregation compared to curcumin, etc., which are not have a pyrazole ring. Therefore, this structure is believed to be closely related to the inhibitory activity against tau protein aggregation.

Pharmacological Test Example 4: In vivo Pharmacokinetics Assessment

SD rats (males, 7 weeks old) were orally administered the test compound (p / o) in an amount of 50 mg / kg body weight or intravenously (iv) in an amount of 1 mg / kg body weight, and blood and brain concentrations were measured within 3 hours. The vehicle for administration was an 80% PEG 400 aqueous solution. Blood was collected under inhalation anesthesia with isoflurane, and the brain was collected after killing the rats. Plasma was separated from the blood. The brain was homogenized after adding a triple volume of PBS, and then methanol was added. The test samples thus obtained were measured. The measurement was carried out by LC-MS / MS (Applied Biosystems and Waters).

Changes in the blood concentration of the compounds of Example 2 and Example 2 (2) ((1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta- 1,6-diene-3,5-dione) after oral administration (po) are shown in FIG. 2. Changes in the concentration of compounds in the brain after intravenous (iv) and oral (po) administration are shown in Table 2. The compound of Example 2 showed higher concentrations in the blood and brain than the compound of Example 2 (2).

table 2 iv 5 minutes iv 180 minutes n / a 60 min. n / a 180 min. Example 2 (2) 5.15 ± 3.34 0.93 ± 0.67 0 18.04 ± 30.79 Example 2 48.66 17.46 8.54 ± 2.93 68.93 ± 39.38 (ng / ml)

Pharmacological Test Example 5: Determination of Inhibitory Activity for Aβ Aggregation and Inhibitory Activity for Aβ Production in Mice by Oral Administration

The APPswe / PS1dE9 Tg mice (males, 10-12 months, n = 8-10) were orally administered the compound of Example 2 and the concentration of Aβ in the brain was measured. The vehicle for administration was an 80% PEG 400 aqueous solution. The dose volume was 10 ml / kg body weight / day, and the dose was adjusted to be 25 mg / kg body weight / day or 50 mg / kg body weight / day . In the vehicle-receiving group, 10 ml / kg body weight / day of an 80% PEG 400 aqueous solution was administered. Administration was carried out using a mouth tube for feeding (Fuchigami Kikai Company) and continued for four weeks. After completion of administration, mice were sacrificed under pentobarbital anesthesia, and the brain was harvested. The brain was homogenized after adding a 10-fold volume of phosphate buffer (pH 7.4), and the homogenate was centrifuged at 4 ° C, 16000 g for 1 hour. The supernatant after centrifugation was used as a sample of soluble protein. The precipitate was resuspended in 70% formic acid, neutralized with a 20-fold volume of 0.9 M Tris buffer (pH 12.0) and used as a sample of insoluble protein. To measure Aβ, a β-amyloid kit (1-42) ELISA (Wako Pure Chemical Industries Co., Ltd.) was used. Samples diluted with a standard solution for dilution by series of dilutions according to the standard curve, each in an amount of 100 μl, were added to the plate with the immobilized primary antibody, and the plate was left at 4 ° C overnight. After washing the plate with wash buffer (5 times), 100 μl HRP-labeled secondary antibody solution was added and the plate was left at 4 ° C for 1 hour. After re-washing the plate with washing buffer (5 times), a TMB solution was added to ensure a chromogenic reaction for 20 minutes. An amount of 100 μl of the reaction stopping solution was added to stop the chromogenic reaction, and light absorption was measured at 450 nm by a microplate reader (Bio-Rad). The concentration of Aβ was determined on the basis of a curve constructed on the basis of the measured values of a series of dilutions according to a standard curve.

The test results are shown in FIG. 3. It was observed that the amounts of insoluble and soluble Aβ 1-42 in the brain decreased in a dose-dependent manner in the group in which the compound of Example 2 was administered (the values in the diagrams are mean ± SEM, ** p <0.01, and One way ANOVA used for reliability criterion).

Pharmacological Test Example 6: Determination of Tau Aggregation Inhibitory Activity in Oral Mice

The tau N279K Tg mice (males, 8 months old, n = 8) were orally administered the compound of Example 2 and the tau concentration in the brain was measured. The vehicle for administration was an 80% aqueous PEG 400 solution. The dose volume was 10 ml / kg body weight / day, and the dose was adjusted to be 10, 20 or 40 mg / kg body weight / day. In the carrier-receiving group, 10 ml / kg body weight / day of an 80% PEG 400 aqueous solution was administered. In the positive control compound group, methylene blue (MB) was adjusted so as to be 40 mg / kg body weight / day . The introduction was carried out using the oral tube for feeding (Fuchigami Kikai Company) and continued for four weeks. After completion of administration, mice were sacrificed under pentobarbital anesthesia, and the brain was harvested. The brain was homogenized after adding 5-fold volume of high-salt buffer (0.8 M NaCl, 1 mm EGTA, 10 mm Tris-HCl, 10% sucrose). Sarkosyl was added to the homogenate so that the sarcosyl concentration was 1%, and the homogenate was incubated at 37 ° C for 1 hour and centrifuged at 4 ° C, 100,000 g, for 1 hour. The pellet was resuspended in extraction buffer (4M guanidine, 50 mM Tris-HCl), diluted with 50 mM Tris-HCl buffer and used as a sample of sarcosyl insoluble protein. To measure tau, a human tau ELISA kit (Invitrogen) was used. Samples diluted with a standard solution for dilution by series of dilutions according to the standard curve, each in an amount of 100 μl, were added to the plate with the immobilized primary antibody, and the plate was left at 4 ° C overnight. After washing the plate with wash buffer, 100 μl of the secondary antibody solution was added, and the plate was left at 4 ° C for 1 hour. After washing the plate again, a solution of HRP-labeled anti-IgG antibody was added, and the tablet was left for 30 minutes. After re-washing the plate with washing buffer, a TMB solution was added to ensure a chromogenic reaction for 20 minutes. An amount of 100 μl of the reaction stopping solution was added to stop the chromogenic reaction, and light absorption was measured at 450 nm by a microplate reader. The tau concentration was determined based on a curve constructed from the measured values of a dilution series according to a standard curve.

The test results for the amount of insoluble tau in the mouse brain are shown in FIG. 4. It was observed that the amount of tau insoluble in sarcosyl in the brain decreased in a dose-dependent manner in the group in which the compound of Example 2 was administered (values in the diagrams are mean ± SEM, ** p <0.01, and One way ANOVA was used for the criterion reliability).

Industrial applicability

The compound of the present invention can be used as a prophylactic agent, therapeutic agent and the like. for the prevention and treatment of Alzheimer's disease, and therefore the present invention can be used in industries such as the pharmaceutical industry.

Claims (34)

1. The compound represented by the following General formula (I):

in which R is hydrogen; Ar ¹ represents a phenyl group having a C _1-3 alkyloxy group substituted with a heterocycloalkyl group selected from the group consisting of tetrahydrofuryl, piperidino, morpholino and piperazino, optionally substituted with a methyl group, a phenyl group having a C _1-3 alkyloxy group substituted with 5 -6-membered heteroaryl group selected from the group consisting of pyridyl, thiazolyl and pyrrole, phenyl group having a C _1-3 alkyloxy group substituted with 1 or 2 phenyl groups, optionally substituted by methoxy, hair battening group having C _1-3 alkyloxy substituted with di (C _1-2 alkyl) amino group, a phenyl group having a C _1-3 alkyloxy group, a substituted alkyl group; or a phenyl group having a disubstituted amino group in which both substituents may be linked together to form a ring; moreover, the above phenyl group in the value of Ar ¹ is unsubstituted or additionally substituted by a substituent selected from the group consisting of a hydroxyl group, a C _1-3 alkyloxy group, a nitro group, a di (alkyl) amino group and bromine; or, alternatively, Ar ¹ represents an indolyl group or a methoxy-phenyl group, and Ar ² represents a phenyl group substituted by one or more substituents selected from the group consisting of an amino group, a hydroxy group, a C _1-2 alkylenedioxy group and a methoxy group unsubstituted or substituted by a pyridyl group; or a heterocyclic group selected from the group consisting of an indolyl group and a benzimidazolyl group, unsubstituted or substituted by one or more C _1-6 alkyl groups, benzyl groups, C _2-7 acyl groups, C _2-7 alkylcarbonyl groups, C _1-6 alkylsulfonyl groups, p-toluenesulfonyl groups, hydroxy groups and nitro groups; or a pharmaceutically acceptable salt thereof. 2. The compound or its pharmaceutically acceptable salt of claim 1, wherein the 5-6 membered heteroaryl group is pyridyl. 3. The compound or its pharmaceutically acceptable salt according to claim 1, in which Ar ¹ represents a 2-methoxy-4- (2-tetrahydrofuranylmethoxy) phenyl group, a 2-methoxy-4- (2-pyridylmethoxy) phenyl group, a 2-hydroxy-4- (2-pyridylmethoxy) phenyl group, 2-methoxy-4 - (2-morpholinoethoxy) phenyl group, 2-benzyloxy-4-diethylaminophenyl group, 5-methoxy-2-nitrophenyl group, 4-benzyloxy-2-methoxyphenyl, 2-bromo-4- (4-methyl-1,4- diazepan-1-yl) phenyl group, 2-methoxy-4- (1,3-thiazol-2-ylmethoxy) phenyl group, 4-diethylamino-2- (2-morpholinoethoxy) phenyl group, 4- (4-methylpiperazine- 1-yl) phenyl group; Ar ² represents a 3-amino-4-hydroxy-phenyl group, a 1,3-benzodioxol-5-yl group, a 1,4-benzodioxan-6-yl group, a 1H-indol-2-yl group, 1H-indol-6 -yl group, 1H-benzimidazol-5-yl group, 1-methyl-1H-indol-6-yl group, 4-nitro-1H-indol-6-yl group and 2-methoxy-4- (2-pyridylmethoxy) phenyl group. 4. The compound or its pharmaceutically acceptable salt of claim 1 or 2, wherein Ar ¹ is a 2-methoxy-4- (2-pyridylmethoxy) phenyl group; Ar ² is a 1H-indol-6-yl group. 5. The compound or its pharmaceutically acceptable salt according to claim 1, which is a compound represented by the formula

its tautomer or its pharmaceutically acceptable salt. 6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar ¹ in the general formula (I) is a phenyl group having a 2- (4-methylpiperazino) ethoxy group or 2-morpholinoethoxy group. 7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar ¹ in the general formula (I) is a 2-methoxy-4- (2-morpholinoethoxy) phenyl group or 4-diethylamino-2- (2-morpholinoethoxy) phenyl group. 8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar ¹ in the general formula (I) is a phenyl group having a pyridin-2-ylmethoxy group. 9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar ¹ in the general formula (I) is a 2-methoxy-4- (pyridin-2-ylmethoxy) phenyl group or 2-hydroxy-4- (pyridin-2 -ylmethoxy) phenyl group. 10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar ² in the general formula (I) is an indol-3-yl group, an indol-6-yl group, a benzimidazol-5-yl group, 1,4-benzodioxan A 6-yl group or a 1,3-benzodioxol-5-yl group which may be unsubstituted or substituted. 11. The compound or its pharmaceutically acceptable salt of claim 10, wherein Ar ² in the general formula (I) is a 1-methylindol-6-yl group or a 4-nitroindol-3-yl group. 12. A tau aggregation inhibitor comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 13. A β-secretase inhibitor comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 14. An amyloid β-protein aggregation inhibitor comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 15. A pharmaceutical composition for treating Alzheimer's disease, comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 16. A method for the prevention or treatment of a disease in which tau, β-secretase or amyloid β-protein is involved, comprising the step of administering an effective amount of a pharmaceutical composition according to claim 15. 17. A method for the prevention or treatment of Alzheimer's disease, comprising the step of administering an effective amount of a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 and one or more pharmacologically acceptable carriers. 18. An oral or parenteral preparation for the treatment of Alzheimer's disease, comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 and one or more pharmacologically acceptable carriers. 19. The method of obtaining the compound or its pharmaceutically acceptable salt according to claim 1 or 2, comprising administering a compound represented by the following general formula (II):

in which each of Ar ¹ and Ar ² has the same meaning as defined in claim 1, or a salt thereof in reaction with a compound represented by the following general formula (III):

in which R has the same meaning as defined in paragraph 1, or its salt.

Images